rs79483201
Variant summary
Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong
The NM_000059.4(BRCA2):c.943T>A(p.Cys315Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000886 in 1,591,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C315F) has been classified as Likely benign.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
Publications
- breast-ovarian cancer, familial, susceptibility to, 2Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
- Fanconi anemia complementation group D1Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
- pancreatic cancer, susceptibility to, 2Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- sarcomaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary breast ovarian cancer syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Fanconi anemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- medulloblastomaInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Benign. The variant received -12 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.943T>A | p.Cys315Ser | missense_variant | Exon 10 of 27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.943T>A | p.Cys315Ser | missense_variant | Exon 10 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893.7 | c.574T>A | p.Cys192Ser | missense_variant | Exon 10 of 27 | 1 | ENSP00000499438.2 | |||
| BRCA2 | ENST00000614259.2 | n.943T>A | non_coding_transcript_exon_variant | Exon 9 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes 0.000177 AC: 27AN: 152160Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000412 AC: 96AN: 232852 AF XY: 0.000342 show subpopulations
GnomAD4 exome AF: 0.0000799 AC: 115AN: 1439120Hom.: 0 Cov.: 31 AF XY: 0.0000727 AC XY: 52AN XY: 715222 show subpopulations
Age Distribution
GnomAD4 genome 0.000171 AC: 26AN: 152278Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15AN XY: 74454 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Benign:8
The BRCA2 p.Cys315Ser variant was identified in 1 of 74 proband chromosomes (frequency: 0.014) from individuals or families with hereditary breast and ovarian cancer (Toh 2008) and in 4 of 534 proband chromosomes (frequency: 0.007) from individuals or families with esophageal cancer (Akbari 2008, Hu 2004). The variant was also identified in dbSNP (ID: rs79483201) as “other,” Clinvitae database (with conflicting interpretations by multiple submitters the ClinVar database (1X as “benign,” 3X as “likely benign,” and 2X as “uncertain significance”), the BIC database (15X with unknown clinical importance), and UMD (14X as ”unclassified variant”). The variant was not found in the Fanconi Anemia Mutation Database (LOVD), LOVD-IARC database, ARUP Laboratories BRCA Mutations Database, COSMIC, or GeneInsight COGR databases. This variant was identified in the 1000 Genomes Project in 8 of 5000 chromosomes (frequency: 0.0016) and in the Exome Aggregation Consortium database (March 14, 2016) in 45 of 120310 chromosomes (freq. 0.0004) in the following populations: East Asian in 44 of 8626 chromosomes (freq. 0.005), South Asian in 1 of 16236 chromosomes (freq. 0.000006), but was not seen in African, Finnish, European (Non-Finnish), and Latino populations, increasing the likelihood this could be a low frequency benign variant. The p.Cys315 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing at the known exon/intron boundary however 3 out of 5 programs suggest a change in a 3’ cryptic splice site. Akbari (2008) classified the variant as deleterious because it is located in the region implicated in the BRCA2-P/CAF complex formation. Hu (2004) classified the variant as uncertain significance because although the variant showed segregation in the families studied, they could not demonstrate co-segregation with disease. In addition, this variant was previously identified by our laboratory in an individual as co-occurring with a pathogenic BRCA2 variant c.8961_8964delGAGT increasing the likelihood that the p.Cys315Ser variant does not have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:5
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
not specified Benign:3
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Variant summary: BRCA2 c.943T>A (p.Cys315Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0005 in 238344 control chromosomes, predominantly at a frequency of 0.0054 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.943T>A has been reported in the literature in sequencing studies of individuals affected with Hereditary Breast and Ovarian Cancer, but it was also present in several healthy controls at the same time (e.g. Ahmad 2012, Haiman 2013, Suter 2004). Moreover, recent case-control studies performed on South-East Asian cohorts indicated that the variant of interest was found with similar frequencies in breast cancer patients and healthy controls (Lai 2017, Yoon 2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Numerous reported co-occurrences with other pathogenic variant(s) have been reported in the BIC and UMD databases (captured verbatim from the database records, BIC - BRCA2 c.5946_5946delT, p.Ser1982Argfs; BRCA1 c.1687C>T, p.Gln563Ter; BRCA1 c.4035_4035delA, p.Glu1345=fs; BRCA1 c.5263_5264insC, p.Ser1755?fs; BRCA1 c.4148C>G, p.Ser1383Ter; UMD - BRCA1 c.3810C>A, p.Cys1270Ter), providing supporting evidence for a benign role. No experimental evidence demonstrating an impact on protein function was ascertained in the context of this classification. Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=4)/likely benign (n=7). Some submitters cite overlapping evidences utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as benign.
Hereditary cancer-predisposing syndrome Benign:3
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Hereditary breast ovarian cancer syndrome Benign:2
The missense variant NM_000059.4(BRCA2):c.943T>A (p.Cys315Ser) has been reported to ClinVar as Benign/Likely benign with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 38241 as of 2025-09-04). There is a moderate physicochemical difference between cysteine and serine. The gene BRCA2 has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 1.00. The p.Cys315Ser missense variant is predicted to be tolerated by both SIFT or PolyPhen2. The nucleotide c.943 in BRCA2 is not conserved according to a GERP++ and PhyloP analysis of 100 vertebrates. For these reasons, this variant has been classified as Benign.
Breast and/or ovarian cancer Benign:1
Fanconi anemia complementation group D1 Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
BRCA2-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Familial cancer of breast Benign:1
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at