ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4261C>T (p.His1421Tyr)

gnomAD frequency: 0.00004  dbSNP: rs80357013
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001084565 SCV000076519 likely benign Hereditary breast ovarian cancer syndrome 2024-01-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131530 SCV000186524 likely benign Hereditary cancer-predisposing syndrome 2019-12-16 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Eurofins Ntd Llc (ga) RCV000679697 SCV000225646 uncertain significance not provided 2015-03-30 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000679697 SCV000296414 likely benign not provided 2022-11-23 criteria provided, single submitter clinical testing
Counsyl RCV000112306 SCV000489251 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2016-09-09 criteria provided, single submitter clinical testing
GeneDx RCV000679697 SCV000729079 likely benign not provided 2021-06-24 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 26689913, 16267036, 21447777, 22682623, 17925560, 12080089, 9333265, 24845084, 18259752, 15689452, 28781887, 30400234, 30765603, 31131967, 15343273, 22737296, 19369211)
PreventionGenetics, part of Exact Sciences RCV000679697 SCV000806948 uncertain significance not provided 2018-01-04 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000131530 SCV000903403 likely benign Hereditary cancer-predisposing syndrome 2022-10-24 criteria provided, single submitter clinical testing
Mendelics RCV000112306 SCV001140530 benign Breast-ovarian cancer, familial, susceptibility to, 1 2023-08-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000174360 SCV001361787 likely benign not specified 2023-08-09 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4261C>T (p.His1421Tyr) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 252434 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4261C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer or at high risk, without strong evidence for causality (examples, Shattuck-Eidens_1997, Dutil_2012, Vogel_2007, Judkins_2005, Diaz-Zabala_2018, Grant_2015, Ren_2021), it has also been reported in a control cohort (example, Dorling_2021). However, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with another pathogenic variant has been reported (Dutil_2012, pathogenic variant not provided) for this variant, supporting evidence for a benign role. Several functional experiments suggest that this variant has transcriptional and HDR activity similar to that of wild-type (Carvalho_2010, Hu_2002, Lu_2015, Woods_2016). The following publications have been ascertained in the context of this evaluation (PMID: 18992264, 30400234, 22682623, 30765603, 25479140, 12080089, 21447777, 16267036, 18259752, 26689913, 15385441, 15689452, 34196900, 9333265, 23704879, 17925560, 28781887). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (likely benign n=5, VUS n=5). Based on the evidence outlined above, the variant was classified as likely benign.
Sema4, Sema4 RCV000131530 SCV002538281 likely benign Hereditary cancer-predisposing syndrome 2022-02-14 criteria provided, single submitter curation
Breast Cancer Information Core (BIC) (BRCA1) RCV000112306 SCV000145044 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 1997-02-15 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000112306 SCV000297610 likely benign Breast-ovarian cancer, familial, susceptibility to, 1 2010-02-03 no assertion criteria provided clinical testing

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