Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_007294.4(BRCA1):c.4963T>C(p.Ser1655Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1655C) has been classified as Uncertain significance.
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
BRCA1 Gene-Disease associations (from GenCC):
breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Our verdict: Pathogenic. The variant received 16 ACMG points.
PM1
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 15 benign, 89 uncertain in NM_007294.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-43070950-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 55333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.874
PP5
Variant 17-43070951-A-G is Pathogenic according to our data. Variant chr17-43070951-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 373826.Status of the report is reviewed_by_expert_panel, 3 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_007294.4. You can select a different transcript below to see updated ACMG assignments.
Hereditary breast ovarian cancer syndromePathogenic:2
Jul 13, 2018
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Data used in classification: The variant was observed in 2 independent UK families undergoing clinical diagnostic testing, the denominator of which dataset of clinical testing was 16,600. Case control comparison against ethnically matched population data (2/16,600 in familial cases against 0/63,369 GNOMAD NFE controls passoc=0.005 pexact= 0.04 (PS4). 3 additional families have been identified in the UK (not included in the previous dataset). The variant is also absent in the remainder of the GNOMAD populations (75,263 individuals) (PM2). Located in BRCT1 domain (PM1_supporting). Non-functional using saturation genome editing in haploid BRCA1 cellular model (Findlay et al 2018, BioARchiv) (PS3_mod). BRCA1 c.4963T>A p.Ser1655Thr independently established as pathogenic (PM5). Additional Information (not included in classification): Predicted deleterious on SIFT but benign on Align GVGD and Polyphen. For substitutions to proline, Align-GVGD is known not to score properly if the variant is in an alpha helix (published data and personal communication, Tavtigian).
Oct 30, 2019
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser1655 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15133502, 15133503, 19200354, 19563646, 24249303, 27767231). This suggests that this residue is clinically-significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces serine with proline at codon 1655 of the BRCA1 protein (p.Ser1655Pro). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a family affected with breast cancer (PMID: 23469205, 29868112). ClinVar contains an entry for this variant (Variation ID: 373826). This variant has been reported to affect BRCA1 protein function (PMID: 12496477, 30209399). This variant is also known as T5082C in the literature.
Breast-ovarian cancer, familial, susceptibility to, 1Pathogenic:1
May 28, 2019
Mendelics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
BRCA1-related cancer predispositionPathogenic:1
Aug 18, 2025
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen
Significance:Likely pathogenic
Review Status:reviewed by expert panel
Collection Method:curation
The c.4963T>C variant in BRCA1 is a missense variant predicted to cause substitution of Serine by Proline at amino acid 1655 (p.(Ser1655Pro)). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMID:30209399, 35196514) (PS3 met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.5, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. A SpliceAI score of 0 predicts no impact on splicing (score threshold <0.10) (PP3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.64 (based on Pathology LR=0.64), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; Internal lab contributor). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PS3, PP3).
Inherited ovarian cancer (without breast cancer)Pathogenic:1
Jun 05, 2025
NHS Central & South Genomic Laboratory Hub
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Breast neoplasmUncertain:1
Clinical and Functional Genomics Group, A.C.Camargo Cancer Center
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:research
not providedUncertain:1
Nov 03, 2021
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Malignant tumor of breastUncertain:1
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing
The BRCA1 p.Ser1655Pro variant was identified in the literature however the frequency of this variant in an affected population was not provided (Flower 2015, Findlay 2018). The variant was also identified in dbSNP (ID: rs1057518639) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by one submitter; as likely pathogenic by Mendelics Analise Genomica; as pathogenic by Cancer Variant Interpretation Group UK). The variant was not identified in LOVD 3.0, UMD-LSDB, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Ser1655 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The variant was identified in DNA methylation profiling to assess pathogenicity of BRCA1 unclassified variants in breast tumor DNA samples and had posterior probability using methylation of only 0.39565 (Flower 2015). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.