ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7402G>A (p.Val2468Ile) (rs730881553)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160129 SCV000210419 uncertain significance not provided 2016-01-18 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7402G>A at the cDNA level, p.Val2468Ile (V2468I) at the protein level, and results in the change of a Valine to an Isoleucine (GTA>ATA). This variant has not, to our knowledge, been published in the literature as either a germline pathogenic variant or a benign polymorphism. However, this variant has been reported as a somatic variant in at least one esophageal tumor (Dulak 2013). BRCA2 Val2468Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Val2468Ile occurs at a position that not conserved and is located within the region of interaction with the FANCD2 (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Val2468Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000217429 SCV000273805 likely benign Hereditary cancer-predisposing syndrome 2020-01-10 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Invitae RCV000538908 SCV000635570 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-11-18 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 2468 of the BRCA2 protein (p.Val2468Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with hereditary breast and ovarian cancer (PMID: 29310832). ClinVar contains an entry for this variant (Variation ID: 182237). 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 isoleucine 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 and their clinical significance is uncertain. 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.
Color Health, Inc RCV000217429 SCV000911804 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001199869 SCV001370608 uncertain significance not specified 2020-05-07 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.7402G>A (p.Val2468Ile) results in a conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain (IPR015252) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251032 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7402G>A has been reported in the literature in at least one individual affected with Hereditary Breast and Ovarian Cancer Syndrome (Apessos_2018). This report however, does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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