Submissions for variant NM_000059.4(BRCA2):c.7985C>T (p.Thr2662Met)

dbSNP: rs431825362

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163213	SCV000213736	benign	Hereditary cancer-predisposing syndrome	2020-07-22	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.
GeneDx	RCV000588790	SCV000279209	uncertain significance	not provided	2018-10-17	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.7985C>T at the cDNA level, p.Thr2662Met (T2662M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). Using alternate nomenclature, this variant would be defined as BRCA2 8213C>T. In a minigene assay, BRCA2 Thr2662Met was shown to result in 3.3% of transcripts skipping exon 18, a naturally occurring isoform (Fraile-Bethencourt 2017). BRCA2 Thr2662Met was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether BRCA2 Thr2662Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081809	SCV000549530	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175366	SCV000695115	benign	not specified	2022-04-09	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7985C>T (p.Thr2662Met) results in a non-conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain (IPR015252) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. 5/5 computational tools predict no significant impact on normal splicing, which was confirmed by one functional study (Fraile-Bethencourt_2017). The variant allele was found at a frequency of 4e-06 in 250098 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7985C>T has been reported in the literature as a VUS in one individual who had personal or family history of breast and/or ovarian cancer (example, Tsaousis_2019) and in control cohorts (example, Dorling_2021). These report(s) does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At-least two co-occurrences with another pathogenic variant has been reported in the UMD database and at our laboratory (UMD-BRCA1 c.5080G>T, p.Glu1694X; our laboratory-BRCA2 c.3915del, p.Phe1305fs), providing supporting evidence for a benign role. At least two publications report experimental evidence evaluating an impact on protein function demonstrating no damaging effect in a homology-directed repair (HDR) assay (example, Hart_2018, Richardson_2021). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. This working group has recommended strong functional evidence (ACMG BS3) as sufficient weightage for categorization as likely benign (Tavtigian_2018). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=4; Likely benign/Benign, n=3). Based on the evidence outlined above, the variant was classified as benign.
GeneKor MSA	RCV000163213	SCV000821947	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163213	SCV000903146	likely benign	Hereditary cancer-predisposing syndrome	2017-04-20	criteria provided, single submitter	clinical testing
Mendelics	RCV004700499	SCV001139200	likely benign	Hereditary cancer	2024-09-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588790	SCV001470450	uncertain significance	not provided	2020-03-05	criteria provided, single submitter	clinical testing
Molecular Endocrinology Laboratory, Christian Medical College	RCV000989069	SCV002030320	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		criteria provided, single submitter	clinical testing