Submissions for variant NM_000059.4(BRCA2):c.3807_3808inv (p.Val1270Ile)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168216	SCV000218882	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1270 of the BRCA2 protein (p.Val1270Ile). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 188253). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193323	SCV001362074	uncertain significance	not specified	2019-11-05	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3807_3808delinsCA (p.Val1270Ile) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 263590 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3807_3808delinsCA in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function has been reported. Co-occurrences with other pathogenic variant(s) have been reported (RAD51C c.773G>A), providing supporting evidence for a benign role. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance.. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV001525206	SCV001735252	uncertain significance	Hereditary cancer-predisposing syndrome	2021-01-05	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 1270 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001525206	SCV003847517	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).
Ambry Genetics	RCV001525206	SCV004052516	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-28	criteria provided, single submitter	clinical testing	The c.3807_3808delTGinsCA variant, located in coding exon 10 of the BRCA2 gene, results from an in-frame deletion of TG and insertion of CA at nucleotide positions 3807 to 3808. This results in the substitution of the valine residue for an isoleucine residue at codon 1270, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.