ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3807_3808invTG (p.Val1270Phefs)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480953 SCV000569698 uncertain significance not provided 2016-03-23 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3807_3808delTGinsCA at the cDNA level and p.Val1270Ile (V1270I) at the protein level. The normal sequence, with the bases that are deleted in braces and inserted in brackets, is CTGT[TG][CA]TTTC. This in frame deletion and insertion, also denoted BRCA2 4035_4036delTGinsCA using alternate nomenclature, occurs on the same allele (in cis) and results in the missense change of a Valine to an Isoleucine (GTT>ATT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Neither BRCA2 3807_3808delTGinsCA nor BRCA2 Val1270I (by this or an alternate nucleotide change) was observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating 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 Val1270I occurs at a position where amino acids with properties similar to Valine are tolerated across species and is located within the Rad51 binding domain (Roy 2012). In addition, in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, we consider BRCA2 Val1270I to be a variant of uncertain significance.
Invitae RCV000168216 SCV000218882 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-12-05 criteria provided, single submitter clinical testing This variant, c.3807_3808delinsCA, is a complex sequence change that replaces valine with isoleucine at codon 1270 of the BRCA2 protein (p.Val1270Ile). 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) and has not been reported in the literature in individuals with a BRCA2-related disease. 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. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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