ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2518A>G (p.Ser840Gly) (rs377475866)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167194 SCV000218031 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-17 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000232315 SCV000289761 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces serine with glycine at codon 840 of the BRCA1 protein (p.Ser840Gly). The serine residue is weakly conserved and there is a small physicochemical difference between serine and glycine. This variant is present in population databases (rs377475866, ExAC 0.01%). This variant has been reported in an individual affected with breast cancer (PMID: 20104584). ClinVar contains an entry for this variant (Variation ID: 187463). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000759508 SCV000321420 uncertain significance not provided 2018-05-14 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2518A>G at the cDNA level, p.Ser840Gly (S840G) at the protein level, and results in the change of a Serine to a Glycine (AGT>GGT). Using alternate nomenclature, this variant would be defined as BRCA1 2637A>G. This variant has been observed in at least one individual with breast cancer (Borg 2010). BRCA1 Ser840Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain and a region known to interact with RAD51 (Chen 1998, 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 evidence, it is unclear whether BRCA1 Ser840Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759508 SCV000888869 uncertain significance not provided 2019-01-07 criteria provided, single submitter clinical testing
Color RCV000167194 SCV000909341 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193116 SCV001361737 uncertain significance not specified 2019-12-26 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2518A>G (p.Ser840Gly) 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 4e-06 in 251094 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2518A>G has been reported in the literature in an individual affected with unilateral breast cancer (Borg 2010, Capanu 2011). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At-least one co-occurrence with anoother pathogenic variant has been observed at our laboratory ( BRCA1 c.3756_3759delGTCT , p.Ser1253fsX10), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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