Clinical Variant Report

BRCA1: Frameshift

Allele Frequency: Absent from gnomAD (0 / 152,312 alleles)

Predictor Scores: CADD 38.0 (normalized 0.38), REVEL 0.94, SpliceAI 0.12

ClinVar: Pathogenic

ACMG Criteria: PVS1 (null variant in a gene where loss of function causes disease), PM2 (absent from population databases), PP3 (computational evidence supports pathogenicity), PP5 (ClinVar reports pathogenic)

This frameshift variant in BRCA1 introduces a premature stop codon at position chr17:43094464. The variant is absent from population databases (gnomAD), consistent with a rare deleterious allele. Multiple computational predictors agree on a damaging effect (CADD 38.0, REVEL 0.94). ClinVar independently classifies this variant as Pathogenic based on clinical evidence from multiple submitters. Loss-of-function variants in BRCA1 are a well-established mechanism for hereditary breast and ovarian cancer syndrome.

TP53: Missense

Allele Frequency: 0.000007 (approximately 1 in 143,000 individuals)

Predictor Scores: CADD 32.0 (normalized 0.32), REVEL 0.89, SpliceAI 0.03

ClinVar: Likely pathogenic

ACMG Criteria: PM2 (absent/extremely rare in population databases), PP3 (computational evidence supports pathogenicity), PP5 (ClinVar reports likely pathogenic)

This missense variant in TP53 at chr17:7674220 substitutes a highly conserved residue in the DNA-binding domain. Population frequency is extremely low (AF 0.000007), well below the expected carrier frequency for Li-Fraumeni syndrome. Both CADD (32.0) and REVEL (0.89) predict a deleterious effect. ClinVar classifies this variant as Likely pathogenic. The affected residue falls within a known hotspot region for somatic and germline TP53 mutations.

MLH1: Splice_Site

Allele Frequency: Absent from gnomAD (0 / 152,312 alleles)

Predictor Scores: CADD 28.5 (normalized 0.29), SpliceAI 0.92

ClinVar: Likely pathogenic

Inheritance: Autosomal dominant

ACMG Criteria: PVS1 (splice-site variant with high SpliceAI score predicting loss of function), PM2 (absent from population databases), PP3 (SpliceAI 0.92 strongly predicts splice disruption), PP5 (ClinVar reports likely pathogenic)

This splice-site variant in MLH1 at chr3:37050340 disrupts the canonical donor site of exon 12. SpliceAI assigns a delta score of 0.92, strongly predicting loss of the native splice donor. The variant is absent from gnomAD, consistent with pathogenicity. ClinVar classifies it as Likely pathogenic based on functional studies and segregation data. Loss of MLH1 function underlies Lynch syndrome (hereditary nonpolyposis colorectal cancer).

ATM: Missense

Allele Frequency: 0.00089 (approximately 1 in 1,124 individuals)

Predictor Scores: CADD 24.1 (normalized 0.24), REVEL 0.58, SpliceAI 0.01

ClinVar: Uncertain significance

ACMG Criteria: PP3 (computational evidence provides weak support for pathogenicity)

This missense variant in ATM at chr11:108289632 has a population frequency near the pathogenicity threshold (AF 0.00089). Computational scores are mixed: CADD (24.1) places it in the top 1% genome-wide, but REVEL (0.58) falls in the uncertain range. ClinVar classifies this as VUS. Without stronger segregation or functional data, this variant remains of uncertain significance.

CHEK2: Missense

Allele Frequency: 0.0045 (approximately 1 in 222 individuals)

Predictor Scores: CADD 22.3 (normalized 0.23), REVEL 0.44, SpliceAI 0.00

ClinVar: Uncertain significance

ACMG Criteria: PP3 (weak computational support)

This missense variant in CHEK2 at chr22:28695868 has a population frequency slightly above the rare disease threshold. REVEL (0.44) falls below the pathogenicity cutoff, and SpliceAI predicts no splice impact. ClinVar lists this as VUS. The relatively common population frequency and modest computational scores suggest this is unlikely to be a high-penetrance pathogenic allele, though moderate-risk contributions cannot be excluded.