ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3661T>C (p.Ser1221Pro) (rs80358611)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195368 SCV000072251 likely benign Hereditary breast and ovarian cancer syndrome 2020-09-29 criteria provided, single submitter clinical testing
Ambry Genetics RCV000132318 SCV000187404 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-10 criteria provided, single submitter clinical testing The p.S1221P variant (also known as c.3661T>C), located in coding exon 10 of the BRCA2 gene, results from a T to C substitution at nucleotide position 3661. The serine at codon 1221 is replaced by proline, an amino acid with similar properties. Alterations in the BRC motifs of BRCA2, such as p.S1221P, may prevent binding of RAD51 and affect the homologous recombination function of BRCA2 (Michalak M, et al. Wspolczesna Onkol 2011; 15 (5): 309–316). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000044238 SCV000210594 likely benign not specified 2017-10-11 criteria provided, single submitter clinical testing 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.
Counsyl RCV000077310 SCV000488983 uncertain significance Breast-ovarian cancer, familial 2 2016-07-29 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000044238 SCV000602863 uncertain significance not specified 2017-02-19 criteria provided, single submitter clinical testing
Color Health, Inc RCV000132318 SCV000683569 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000044238 SCV000916885 uncertain significance not specified 2018-03-20 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.3661T>C (p.Ser1221Pro) results in a non-conservative amino acid change located in the BRCA2 repeat (IPR002093) of the encoded protein sequence. This is one of the BRCA repeats that is critical for binding to RAD51 (a key protein in DNA recombinational repair) and resistance to methyl methanesulphonate treatment (IPR002093). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 245272 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (1.2e-05 vs 7.50e-04), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.3661T>C in individuals affected with Hereditary Breast and Ovarian Cancer has been reported. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.7007G>A, p.Arg2336His), providing supporting evidence for a benign role, however without additional clinical information. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Tal_2009). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (5 VUS, 1 likely benign). Based on the evidence outlined above, the variant was classified as uncertain significance.
Sharing Clinical Reports Project (SCRP) RCV000077310 SCV000109107 likely benign Breast-ovarian cancer, familial 2 2012-12-11 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077310 SCV000146272 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing

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