ClinVar Miner

Submissions for variant NM_007294.3(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 RCV000858856 SCV000076656 likely benign not provided 2019-01-24 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131514 SCV000186508 likely benign Hereditary cancer-predisposing syndrome 2017-12-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other data supporting benign classification,Subpopulation frequency in support of benign classification,In silico models in agreement (benign)
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
Integrated Genetics/Laboratory Corporation of America RCV000212185 SCV000699168 likely benign not specified 2019-07-26 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 7.9e-05 in 254256 control chromosomes, predominantly at a frequency of 0.00054 within the East Asian subpopulation in the gnomAD database. This frequency is close to the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (i.e. 5.4e-04 vs. 1e-03). 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 2.5e-03 (HGVD), 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. In one of these publications, authors classified the variant as "likely benign" based on odds ratios using data obtained from Korean population controls (Park_ 2017). At least one publication reported experimental evidence evaluating an impact on protein function, and showed that the variant protein has a slightly stronger transcriptional activity than the wild type; therefore authors classified the variant as "not likely pathogenic" (Woods 2016). Co-occurrence with another pathogenic variant has been reported (ATM c.7456C>T, p.Arg2486X), providing supporting evidence for a benign role. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant with conflicting classifications, "likely benign/benign" (4x) and "uncertain significance" (2x). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000048643 SCV000839228 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color 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
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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