ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4036G>A (p.Glu1346Lys) (rs80357407)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001081659 SCV000076427 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-25 criteria provided, single submitter clinical testing
GeneDx RCV000048414 SCV000209965 likely benign not specified 2017-12-06 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.
Ambry Genetics RCV000164474 SCV000215119 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000048414 SCV000699100 benign not specified 2021-04-19 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4036G>A (p.Glu1346Lys) results in a 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. Studies reporting interspecific sequence variation analysis consider this variant as 'likely to be neutral or of little clinical significance (example, Abkevich_2004). The variant allele was found at a frequency of 4.4e-05 in 251112 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (4.4e-05 vs 0.001), allowing no conclusion about variant significance. c.4036G>A has been reported in the literature in individuals affected with Breast and/or Ovarian Cancer (example, Judkins_2005, Konecny_2011, Stoppa-Lyonnet_1997, Kluska_2015, Anczukow_2008, Wong-Brown_2015, Lu_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (MSH2 c.10C>T, p.Gln4*), providing supporting evidence for a benign role. Multiple publications report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in its ability to complement Brca1-deficient mouse embryonic stem cells in HRR (homologous recombination repair), using cisplatin and olaparib sensitivity assays and a direct repeat GFP (DR-GFP) HRR assay as well as a separate HDR (homology directed repair) assay (example, Nouwman_2013,, Lu_2015, Bouwman_2020). 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 benign (n=1)/likely benign (n=4). Based on the evidence outlined above, the variant was classified as benign.
Color Health, Inc RCV000164474 SCV000910725 benign Hereditary cancer-predisposing syndrome 2016-02-10 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590201 SCV001133574 likely benign not provided 2020-08-13 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287283 SCV001473958 likely benign none provided 2020-01-30 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031142 SCV000053741 benign Breast-ovarian cancer, familial 1 2009-12-28 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031142 SCV000144939 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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