ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3731T>C (p.Ile1244Thr) (rs730881526)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586904 SCV000210322 uncertain significance not provided 2018-05-16 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3731T>C at the cDNA level, p.Ile1244Thr (I1244T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). This variant, also known as 3959T>C using alternate nomenclature, was observed in at least one individual with triple negative breast cancer (Wong-Brown 2015). BRCA2 Ile1244Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the BRC2 functional domain and the region that binds to RAD51 (Cole 2011, Roy 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA2 Ile1244Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000165364 SCV000216090 uncertain significance Hereditary cancer-predisposing syndrome 2016-04-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000165364 SCV000688830 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586904 SCV000694713 uncertain significance not provided 2017-05-30 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.3731T>C (p.Ile1244Thr) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution in one of the BRCA2 repeat domains (InterPro). 3/4 in silico tools predict a damaging outcome for this variant. This variant is absent from the large control database ExAC (0/119920 control chromosomes), but is identified in gnomAD dataset (2/242492 chrs tested). The variant was identified in a breast cancer patient without strong evidence of pathogenicity (Wong-Brown_BRCA1&2_BCRT_2015). Two clinical diagnostic laboratories have classified this variant as one of uncertain significance. Taken together, this variant is classified as a VUS until additional information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586904 SCV000887795 uncertain significance not provided 2018-02-23 criteria provided, single submitter clinical testing
Invitae RCV000824375 SCV000965271 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-08-20 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 1244 of the BRCA2 protein (p.Ile1244Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in individuals affected with breast cancer (PMID: 25682074). ClinVar contains an entry for this variant (Variation ID: 182203). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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