ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2804T>G (p.Val935Gly) (rs4988356)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000213879 SCV000273661 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-31 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (benign)
GeneDx RCV000656815 SCV000329162 uncertain significance not provided 2018-11-19 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.2804T>G at the cDNA level, p.Val935Gly (V935G) at the protein level, and results in the change of a Valine to a Glycine (GTG>GGG). This variant, also published as 2945T>G using alternate nomenclature, was reported in an individual diagnosed with breast cancer below age 35 (Rutter 2003), but Easton et al. (2016) found this variant to occur at similar frequency in breast cancer cases and controls (p=0.51). BRIP1 Val935Gly was observed at an allele frequency of 0.14% (44/30,778) in individuals of South Asian ancestry in large population cohorts (Lek 2016). BRIP1 Val935Gly is located in the BRCA1 binding domain (Cantor 2001). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRIP1 Val935Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000468023 SCV000547290 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-12-16 criteria provided, single submitter clinical testing This sequence change replaces valine with glycine at codon 935 of the BRIP1 protein (p.Val935Gly). The valine residue is weakly conserved and there is a moderate physicochemical difference between valine and glycine. This variant is present in population databases (rs4988356, ExAC 0.1%). This variant has been observed in an individual affected with breast cancer (PMID: 12872252). This variant is also known as 2945T>G in the literature. ClinVar contains an entry for this variant (Variation ID: 133757). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The glycine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. 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.
Counsyl RCV000662595 SCV000785225 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2017-06-21 criteria provided, single submitter clinical testing
Color RCV000213879 SCV000903027 likely benign Hereditary cancer-predisposing syndrome 2016-07-20 criteria provided, single submitter clinical testing
ITMI RCV000120401 SCV000084553 not provided not specified 2013-09-19 no assertion provided reference population

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