Submissions for variant NM_000059.4(BRCA2):c.5885T>C (p.Ile1962Thr)

gnomAD frequency: 0.00001  dbSNP: rs1060502377

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000457036	SCV000549483	likely benign	Hereditary breast ovarian cancer syndrome	2023-10-09	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000499719	SCV000593748	uncertain significance	not specified	2017-02-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000564384	SCV000668584	likely benign	Hereditary cancer-predisposing syndrome	2018-02-27	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.
Mendelics	RCV000457036	SCV000838824	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770729	SCV000902210	uncertain significance	Breast and/or ovarian cancer	2021-06-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000564384	SCV000910249	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-11	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 1962 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least four individuals affected with breast and/or ovarian cancer (PMID: 29684080, 31409081, 32438681, 35150867). In a breast cancer case-control meta-analysis, this variant showed inconclusive association with breast cancer (0/60466 case and 3/53458 controls) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001812). This variant also has been detected in an individual age 70 years or older without cancer (FLOSSIES database). This variant has been identified in 3/282368 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000499719	SCV000917030	uncertain significance	not specified	2021-09-03	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5885T>C (p.Ile1962Thr) 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 8e-06 in 250974 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5885T>C has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Zuntini_2018, Azzollini_2016, Machackova_2019, Santonocito_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrence with a pathogenic variant has been reported (BRCA2 c.8904delC, p.Val2969CysfsX7), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Likely benign n=1, VUS n=6). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Mendelics	RCV000989045	SCV001139130	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000564384	SCV003850750	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).
Department of Medical and Surgical Sciences, University of Bologna	RCV000989045	SCV004228423	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)