Final classification

Likely Benign

PP4BP1

BRCA2

c.4183G>T

p.Ala1395Ser

missense

Gene context NCBI Gene ↗ OncoKB ↗

BRCA2 encodes a DNA repair protein that maintains genome stability by repairing double-strand breaks through homologous recombination and by protecting DNA replication forks. It acts as a tumor suppressor, and inherited loss-of-function changes cause hereditary breast and ovarian cancer syndrome, with elevated lifetime risks of breast, ovarian, prostate, and pancreatic cancers; biallelic changes cause Fanconi anemia complementation group D1. Reduced or altered BRCA2 activity is implicated in multiple tumor types, and PARP inhibitors are an approved treatment for BRCA2-associated ovarian and breast cancers.

This variant

BRCA2's cancer risk arises from loss-of-function changes that impair its DNA-repair and tumor-suppressor activity. This missense change (p.Ala1395Ser) is predicted not to disrupt that function: it lies outside the protein's clinically important domains, has no predicted splicing impact, and is essentially absent from population databases. The Likely Benign classification therefore indicates this variant is not expected to impair BRCA2 function or raise the hereditary breast and ovarian cancer risk associated with this gene.

Transcript

NM_000059.4

HGVS · transcript:coding

NM_000059.4:c.4183G>T

GRCh38

chr13:32338538 G>T

GRCh37

chr13:32912675 G>T

Likely Benign: conflicting-evidence net score -3 (PP4 Supporting +1, BP1 Strong -4) falls in the -6 to -2 Likely Benign range.

Classification rationale

PP4 BP1 Likely Benign

BRCA2 c.4183G>T missense

PP4 (Supporting): ENIGMA combined multifactorial likelihood LR 2.225 for this exact variant meets the >=2.08 supporting threshold. BP1 (Strong): missense p.Ala1395Ser lies outside BRCA2's clinically important functional domains with no predicted splicing impact (SpliceAI max delta 0.00). Overall Likely Benign: conflicting-evidence point scoring (PP4 +1, BP1 -4, net -3) places the variant in the -6 to -2 Likely Benign range.

PP4 + BP1 → Likely Benign

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_000059.4 · variants mapped to exon structure

BRCA2 NM_000059.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 15 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PP4 supporting Pathogenic

Met (Supporting): ENIGMA combined multifactorial likelihood LR 2.225 for this exact variant meets the >=2.08 threshold.

ENIGMA BRCA1/BRCA2 VCEP specification v1.2 (CSPEC 1535438831) PP4 rule: 'Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data. PP4 - LR >=2.08' (Supporting); neutral zone 'Combined LR >0.48 and <2.08 doesn't provide supporting evidence in either direction (PP4 and BP5 not applicable)'.Parsons et al. 2019 (PMID:31131967) Supplementary Table 1 (HUMU-40-1557-s001.xlsx, sheet 1): BRCA2 c.4183G>T, p.Ala1395Ser - pathology LR 1.07, co-occurrence LR 1.0246153856, family history LR 2.0294847967, Combined LR (Odds for Causality) 2.2250022419453646, prior 0.02, posterior 4.3435864217950808E-2 (IARC 'Uncertain'). Combined LR >=2.08 -> PP4 Supporting.Li et al. 2020 (PMID:31853058) clinical-history LR table (vcep_pmid_31853058_brca2_clinical_history_lr): c.4183G>T LR = 0.7929228517802025 (N=1 proband) - neutral zone, component not applied to avoid double counting family/personal history already integrated in the combined LR.

cspec ↗PMID:31131967 ↗PMID:31853058 ↗

BP1 strong Benign

Met (Strong): missense p.Ala1395Ser lies outside BRCA2's functional domains with SpliceAI max delta 0.00.

ENIGMA BRCA1/BRCA2 VCEP specification v1.2 (cspec, doc 1535438831): BP1_Strong rule - missense variants outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI <= 0.1); domains defined as BRCA2 PALB2 binding domain aa 10-40 and BRCA2 DNA binding domain aa 2481-3186.SpliceAI lookup (spliceai): max delta score = 0.00 <= 0.1 - no predicted splicing impact.Variant normalization (prefetch.json / case_summary.json): p.Ala1395Ser; residue 1395 is not within aa 10-40 or aa 2481-3186.

cspec ↗spliceai ↗PMID:31911673 ↗

Assessed · not applied · 9 not met · 6 not assessed

Pathogenic

PS1 Not met: no pathogenic or likely pathogenic variant producing the same p.Ala1395Ser change exists (0 comparator candidates).

PS2 Not assessed: no parental testing or documentation of de novo occurrence was available.

PS3 Not met: no well-established functional studies supporting a damaging effect exist for this variant.

PS4 Not assessed: no case-control or prevalence data for this exact variant was available.

PM2 Not met: present in gnomAD v4.1 (AF 1.7e-06), so the strict absence requirement of PM2 is not demonstrated.

PM6 Not assessed: no evidence that the variant arose de novo.

PP1 Not assessed: no family segregation data or quantitative co-segregation likelihood ratio was available.

PP3 Not met: BayesDel no-AF -0.32 falls below the 0.30 threshold and SpliceAI max delta 0.00 below 0.2.

Benign

BA1 Not met: gnomAD FAF 2.8e-07 is far below the >0.1% BA1 threshold.

BS1 Not met: gnomAD FAF 2.8e-07 is below even the 0.002% BS1-Supporting threshold.

BS2 Not assessed: no proband phenotype data to score the ENIGMA BS2 points table.

BS3 Not met: no well-established functional assay demonstrates no damaging effect on protein function.

BS4 Not assessed: no co-segregation or non-segregation likelihood ratio data was available.

BP4 Not met: p.Ala1395Ser lies outside the BRCA2 functional domains, failing BP4's domain-location requirement.

BP5 Not met: combined LR 2.225 is in the pathogenic direction, above the <=0.48 BP5 threshold.

N/A · 11 PVS1 · PM1 · PM3 · PM4 · PM5 · PP2 · PP5 · BP2 · BP3 · BP6 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.24747e-06; MAF= 0.00012%, 2/1603248 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.70022e-06; MAF= 0.00017%, 2/1176318 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00012% · 2 / 1,603,248
0 hom · FAF 2.8e-05%

European (non-Finnish)

2 / 1,176,318

0.00017%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (10 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 96805)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.099. BayesDel score = -0.321456.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA2, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

3papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 5 further PMIDs triaged but not cited — see Sources & references.

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification.

PMID 31131967 ↗ · Parsons MT et al. · 2019 Sep CLINVAR · splicing rna

Searched

c.4183G>Tp.Ala1395SerA1395S4183

Found

ENIGMA large-scale multifactorial likelihood analysis (Parsons et al. 2019). Direct lookup of BRCA2 c.4183G>T (p.Ala1395Ser) in the accompanying supplementary workbook (HUMU-40-1557-s001.xlsx): no BRCA2 row exists in Supplementary Table 1 'All Data' - the only c.4183G>T / p.(Ala1395Ser) row is BRCA1 (legacy description 4411G>T, combined LR 2.225, prior 0.02, posterior 0.043, IARC Uncertain). Supplementary Table 2 'Data Sources' lists BRCA2 c.4183G>T twice (source 'Easton et al 2007 dataset' and source 'Edinir Palmero') with EMPTY co-segregation family counts (one family-history-score count and one breast-tumour count respectively). No combined LR or co-segregation LR is therefore available for BRCA2 c.4183G>T, so PP1/BS4 cannot be quantified from this resource.

Variant

✓ Names this variant — characterised directly

Applied to

→PP4 supporting

Combined LR 2.225 for the exact variant (in companion SuppT1) meets the ENIGMA PP4 Supporting threshold of LR >=2.08.

Source: 'Easton et al 2007 dataset', Gene: 'BRCA2', Variant: 'c.4183G>T', Co-Segregation Family Count: (empty), Breast Tumour Count: (empty), Family History Score Family Count: '1' | Source: 'Edinir Palmero', Gene: 'BRCA2', Variant: 'c.4183G>T', Co-Segregation Family Count: (empty), Breast Tumour Count: '1', Family History Score Family Count: (empty)

Location HUMU-40-1557-s001.xlsx, Supplementary Table 2 'Data Sources' rows 708 and 1263 (columns: Source, Gene, Variant, Co-Segregation Family Count, Breast Tumour Count, Family History Score Family Count); absence of a BRCA2 row verified across Supplementary Table 1 'All Data' · Context ENIGMA multifactorial likelihood model for BRCA1/BRCA2 missense and splice variants combining segregation, pathology, co-occurrence, family history and case-control components with prior probability of pathogenicity and IARC 5-class output · full text

Rule & framework references · cited for criterion definitions, not variant evidence

31853058 ↗ Classification of variants of uncertain significance in BRCA1 and BRCA2 using personal and family history of cancer from individuals in a large hereditary cancer multigene panel testing cohort.

31911673 ↗ Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots".

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 5 PMIDs not cited in assessment

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

17508274 ↗ Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors. CLINVAR

19305347 ↗ ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome. CLINVAR

23788249 ↗ ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. CLINVAR

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