ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2123C>A (p.Ser708Tyr) (rs80357182)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129531 SCV000184307 likely benign Hereditary cancer-predisposing syndrome 2019-04-22 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
GeneDx RCV000314335 SCV000329124 uncertain significance not provided 2018-06-26 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2123C>A at the cDNA level, p.Ser708Tyr (S708Y) at the protein level, and results in the change of a Serine to a Tyrosine (TCT>TAT). Using alternate nomenclature, this variant would be defined as BRCA1 2242C>A. This variant has been observed in individuals with breast cancer, and displayed homology directed repair activity comparable to wild-type in an in vitro functional study (Lu 2015, Azzolini 2016). BRCA1 Ser708Tyr was observed at an allele frequency of 0.04% (12/30,780) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is located in the DNA binding domain and the RAD50 and STAT1 binding domains (Zhong 1999, Ouchi 2000, Narod 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether BRCA1 Ser708Tyr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Mendelics RCV000709482 SCV000839274 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129531 SCV000910913 likely benign Hereditary cancer-predisposing syndrome 2016-11-15 criteria provided, single submitter clinical testing
Mendelics RCV000031028 SCV001140584 uncertain significance Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193139 SCV001361783 likely benign not specified 2021-01-11 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2123C>A (p.Ser708Tyr) 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 6.8e-05 in 251170 control chromosomes, predominantly at a frequency of 0.00039 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (6.8e-05 vs 0.001), allowing no conclusion about variant significance. c.2123C>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (example, Judkins_2005, Coulet_2010, Azzollini_2016). At-least one report of this variant co-occurring with a pathogenic variant (c.2062C>T, p.Gln688*) in the PTCH1 gene as an alternate molecular basis of disease in an individual with Gorlin syndrome has been reported (Paulo_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least two publications reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant protein had comparable homology-directed repair (HDR) activity to the wild type (Lu_2015) and a neutral impact in homologous recombination repair complementation assays (Bouwman_2020). Four ClinVar submissons from clinical diagnostic laboratories (evaluation after 2014) cites the variant twice as uncertain significance and twice as likely benign. Based on the evidence outlined above, the variant was re-classified as likely benign.
Invitae RCV000709482 SCV001696861 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-06 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031028 SCV000053622 uncertain significance Breast-ovarian cancer, familial 1 2009-04-03 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031028 SCV000144307 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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