Submissions for variant NM_007294.4(BRCA1):c.2006T>C (p.Met669Thr)

gnomAD frequency: 0.00002  dbSNP: rs80356895

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130064	SCV000184891	likely benign	Hereditary cancer-predisposing syndrome	2022-09-09	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.
Counsyl	RCV000031023	SCV000487917	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2015-12-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000420884	SCV000518172	likely benign	not specified	2018-01-03	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.
Color Diagnostics, LLC DBA Color Health	RCV000130064	SCV000911034	likely benign	Hereditary cancer-predisposing syndrome	2016-09-23	criteria provided, single submitter	clinical testing
Mendelics	RCV000031023	SCV001140587	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001472789	SCV001676927	benign	Hereditary breast ovarian cancer syndrome	2024-12-24	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800318	SCV002046150	likely benign	not provided	2023-01-30	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130064	SCV003849569	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000420884	SCV004021077	uncertain significance	not specified	2023-06-06	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2006T>C (p.Met669Thr) 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 7.6e-05 in 262638 control chromosomes (gnomAD, Dong_2021). This frequency is not significantly higher than estimated for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (7.6e-05 vs 0.001), allowing no conclusion about variant significance. c.2006T>C has been reported in the literature in individuals affected with Breast Cancer (e.g. Sun_2014) and Prostate Cancer (e.g. Tang_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32467295, 33087888, 25337278, 35734583). Eight ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, five as likely benign, and two as benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
All of Us Research Program, National Institutes of Health	RCV000031023	SCV004818239	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-10	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031023	SCV000053616	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2012-02-17	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031023	SCV000144273	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-11-25	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000031023	SCV000591363	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing	The BRCA1 p.Met669Thr variant was identified in 4 of 926 proband chromosomes (frequency: 0.004) from individuals or families with breast cancer and was not identified in 60 control chromosomes from healthy individuals (Sun 2014). The variant was also identified in dbSNP (ID: rs80356895) as "With other allele" and ClinVar (classified as benign by SCRP; as likely benign by GeneDx; and as uncertain significance by Ambry Genetics, Counsyl, COGR and BIC). The variant was not identified in LOVD 3.0 or UMD-LSDB databases. The variant was identified in 12 of 276982 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 1 of 126578 chromosomes (freq: 0.000008) and East Asian in 11 of 18862 chromosomes (freq: 0.0006), but not in the African, Other, Latino, Ashkenazi Jewish, Finnish, or South Asian populations. The p.Met669 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Center for Precision Medicine, Meizhou People's Hospital	RCV002250471	SCV002520891	uncertain significance	Familial cancer of breast		no assertion criteria provided	literature only