Submissions for variant NM_007294.4(BRCA1):c.4955T>C (p.Met1652Thr)

gnomAD frequency: 0.00002  dbSNP: rs80356968

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031196	SCV000244373	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-08-10	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.00011
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195346	SCV000076721	benign	Hereditary breast ovarian cancer syndrome	2025-01-11	criteria provided, single submitter	clinical testing
GeneDx	RCV001719706	SCV000209981	likely benign	not provided	2020-09-17	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25782689, 20516115, 17305420, 15184261, 21990134, 17924331, 9585608, 25085752, 15172985, 12457999, 15004537, 27272900, 28781887, 30209399, 30765603, 33087888)
Ambry Genetics	RCV000162990	SCV000213478	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: 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	RCV000031196	SCV000220544	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-07-23	criteria provided, single submitter	literature only
Color Diagnostics, LLC DBA Color Health	RCV000162990	SCV000683230	likely benign	Hereditary cancer-predisposing syndrome	2017-01-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048708	SCV000918687	benign	not specified	2021-03-28	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4955T>C (p.Met1652Thr) results in a non-conservative amino acid change located in the BRCT domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Several computational studies predicted a neutral outcome for the variant (Pruss 2014, Carvalho 2014, Woods 2016), though one study predicted the variant to be deleterious (Karchin 2007). A study based on comparative evolutionary methods predicted a deleterious outcome for this variant (p.Met1652Thr) and another variant affecting this amino acid position (p.Met1652Ile) (Pavlicek 2004), however p.Met1652Ile (c.4956G>A) was classified as benign by our laboratory, indicating that missense changes might tolerated at this position. The variant allele was found at a frequency of 2e-05 in 250978 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4955T>C has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer (example, Huusko 1998, Meindl 2002, Solano 2013). 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 (BRCA2 c.1813dupA, p.I605fs*11), providing supporting evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function. In an in vitro functional study the variant was reported to have no functional effect on transcriptional activation, phosphopeptide binding and limited proteolysis (that was used to assess the protein folding stability) (Lee 2010), however another study assessing proliferation rate of yeast cell transformants indicated a possible functional defect (Coyne 2004), though this later assay does not provide a direct evidence on protein function. Indeed, a later in vitro study found that this variant (Met1652Thr) cannot be correctly classified by these type of yeast assays (Thouvenot 2016). More recently this variant was not found to have any impact on homology directed repair (HDR) in a high throughput assay utilizing saturation genome editing (example, Findlay_2018). Multifactorial probability models, performing systematic assessments of variants of unknown significance in the BRCA genes, which included analysis of co-occurrence in trans with known deleterious mutations, personal and family history of cancer, and co-segregation with disease in pedigrees predicted this variant to be neutral (Easton 2007 and Lindor 2012). Multiple clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as benign (n=2, including expert panel)/likely benign (n=4). Based on the evidence outlined above, the variant was classified as benign.
Mendelics	RCV000031196	SCV001140500	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000048708	SCV002070679	likely benign	not specified	2019-05-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004802988	SCV004817611	likely benign	BRCA1-related cancer predisposition	2024-08-30	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031196	SCV000053796	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2010-06-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031196	SCV000145221	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000162990	SCV000787907	likely benign	Hereditary cancer-predisposing syndrome	2017-08-28	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000031196	SCV001243266	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro