Submissions for variant NM_000059.4(BRCA2):c.2671G>C (p.Val891Leu)

gnomAD frequency: 0.00002  dbSNP: rs756951335

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000198310	SCV000254175	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 891 of the BRCA2 protein (p.Val891Leu). This variant is present in population databases (rs756951335, gnomAD 0.02%). This missense change has been observed in individual(s) with breast, ovarian cancer, or colon cancer (PMID: 30093976, 35918668). ClinVar contains an entry for this variant (Variation ID: 216241). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. 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.
Ambry Genetics	RCV000575746	SCV000668678	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-05	criteria provided, single submitter	clinical testing	The p.V891L variant (also known as c.2671G>C), located in coding exon 10 of the BRCA2 gene, results from a G to C substitution at nucleotide position 2671. The valine at codon 891 is replaced by leucine, an amino acid with highly similar properties. This alteration was detected in 1/1664 Chinese Hakka patients with breast and/or ovarian cancer (Zhang Y et al. BMC Cancer, 2022 Aug;22:842). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000575746	SCV000905158	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-25	criteria provided, single submitter	clinical testing	This missense variant replaces valine with leucine at codon 891 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been identified in at least one individual affected with breast cancer and two unaffected individuals (PMID: 30093976, 33471991; Leiden Open Variation Database DB-ID BRCA2_007975). This variant has been identified in 4/232918 chromosomes 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.
GeneDx	RCV001567191	SCV001790834	uncertain significance	not provided	2019-12-23	criteria provided, single submitter	clinical testing	Observed in individuals with multiple primary cancers (Chan 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Also known as 2899G>C; This variant is associated with the following publications: (PMID: 30093976)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000575746	SCV003848488	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).
All of Us Research Program, National Institutes of Health	RCV003996986	SCV004845043	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces valine with leucine at codon 891 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been identified in at least one individual with breast cancer, though has also been identified in clinically healthy individuals (PMID: 30093976, 33471991; Leiden Open Variation Database DB-ID BRCA2_007975). This variant has been identified in 4/232918 chromosomes 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.
3DMed Clinical Laboratory Inc	RCV000677822	SCV000803982	uncertain significance	Cancer of the pancreas	2017-01-16	no assertion criteria provided	clinical testing
Center for Precision Medicine, Meizhou People's Hospital	RCV002250593	SCV002520771	uncertain significance	Familial cancer of breast		no assertion criteria provided	literature only