Submissions for variant NM_007294.4(BRCA1):c.230C>T (p.Thr77Met)

gnomAD frequency: 0.00001  dbSNP: rs80357209

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216581	SCV000276530	likely benign	Hereditary cancer-predisposing syndrome	2021-08-06	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
GeneDx	RCV000587004	SCV000572470	uncertain significance	not provided	2021-09-16	criteria provided, single submitter	clinical testing	Observed in individuals with breast cancer or thyroid cancer (Fackenthal 2012, Yehia 2018); Published functional studies demonstrate decreased E2 binding and E3 ligase activity, but no impact on BARD1 binding, HDR activity, or cell survival (Morris 2006, Findlay 2018, Starita 2018, Caleca 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (Lek 2016); Also known as 349C>T; This variant is associated with the following publications: (PMID: 22034289, 29684080, 20104584, 24389207, 30219179, 30696104, 30209399, 29106415, 15385441, 20016594, 25823446, 16267036, 27720647, 24489791, 21309043, 26761715, 16403807)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230384	SCV000698938	likely benign	not specified	2023-04-03	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.230C>T (p.Thr77Met) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251146 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.230C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer without strong evidence for pathogenicity (example: Fackenthal_2012; Judkins_2005). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.4484G>T , p.Arg1495Met), providing supporting evidence for a benign role (BIC database). Multiple functional studies (including HDR assay assessement) have reported this variant as functional (example: Findlay_2018 and Clark_2022). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=6) and benign/likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl	RCV000077514	SCV000785427	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-08-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587004	SCV000888863	uncertain significance	not provided	2023-03-26	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000026 (3/113612 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 22034289 (2012), 16267036 (2005), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA1)), as well as in an unaffected individual (PMID: 32467295 (2020)). Functional studies have reported this variant had no effect on BARD1 binding (PMID: 30696104 (2019), 35659930 (2022)), BRCA1 splicing (PMID: 26761715 (2016), 21309043 (2011)), or BRCA1 SUMOylation (PMID: 20016594 (2009)). One functional study also reported normal function in haploid cells and little to no change to RNA levels (PMID: 30209399 (2018)). However, one functional study reported reduced ubiquitin ligase activity (PMID: 25823446 (2015), 16403807(2006)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Illumina Laboratory Services, Illumina	RCV000077514	SCV001285182	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color Diagnostics, LLC DBA Color Health	RCV000216581	SCV001351368	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-21	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 77 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported that this variant does not impact BRCA1 function in a homology-directed repair and a haploid cell proliferation assay (PMID: 30209399, 30219179), and functional studies on ubiquitin-related activities also have reported partial to no impact (PMID: 16403807, 30696104). This variant has been reported in at least one individual each affected with breast, prostate and thyroid cancer (PMID: 22034289, 29684080, 31214711, 33471991; Leiden Open Variation Database DB-ID BRCA1_000065). This variant has been identified in 4/251146 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae	RCV001326176	SCV001517191	benign	Hereditary breast ovarian cancer syndrome	2023-12-13	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149702	SCV003838254	uncertain significance	Breast and/or ovarian cancer	2022-01-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000077514	SCV004212720	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-10-13	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003230384	SCV004242853	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077514	SCV000109314	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2012-09-20	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077514	SCV000144745	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000077514	SCV001238125	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro