ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4729T>C (p.Ser1577Pro) (rs80356909)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048643 SCV000076656 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-24 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131514 SCV000186508 likely benign Hereditary cancer-predisposing syndrome 2018-12-05 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification;Subpopulation frequency in support of benign classification
GeneDx RCV000212185 SCV000209975 likely benign not specified 2017-09-06 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000858856 SCV000605890 likely benign not provided 2019-02-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212185 SCV000699168 benign not specified 2020-10-15 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4729T>C (p.Ser1577Pro) 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 5.6e-05 in 251842 control chromosomes, predominantly at a frequency of 0.00054 within the East Asian subpopulation in the gnomAD database. This frequency is not higher than the maximum expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (HBOC) Syndrome (0.001). However, in certain East Asian subpopulations the variant was observed with an even higher occurrence, e.g. in the Japanese control population it occurred with a frequency of 0.0055 (jMorp database), suggesting a benign role for the variant. The variant, c.4729T>C, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, as well as in several unaffected controls, who were almost exclusively of East Asian origin. Two recent case-control association studies, involving breast cancer patients and controls of Korean- (Park_2017) and Japanese ancestry (Momozawa_2018), found that the variant is not associated with a significant increase in breast/ovarian cancer risk, and therefore the authors of these studies classified that the variant as likely benign/benign, respectively. Co-occurrences with other pathogenic variants have been reported (ATM c.7456C>T (p.Arg2486X) in Ohmoto_2018; and BRCA2 c.6952C>T (p.Arg2318X), and BRCA2 c.6486_6489delACAA (p.Lys2162AsnfsX5) in two internal LCA samples), providing supporting evidence for a benign role. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant protein had a slightly stronger transcriptional activity than the wild type; therefore, authors classified the variant as "not likely pathogenic" (Woods 2016). Six other 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 (1x) / likely benign (5x). Based on the evidence outlined above, the variant was classified as benign.
Color Health, Inc RCV000131514 SCV000910806 benign Hereditary cancer-predisposing syndrome 2016-01-19 criteria provided, single submitter clinical testing
Mendelics RCV000077585 SCV001140512 likely benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287868 SCV001474609 likely benign none provided 2019-10-11 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077585 SCV000109388 likely benign Breast-ovarian cancer, familial 1 2011-05-27 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077585 SCV000145167 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing

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