Submissions for variant NM_000059.4(BRCA2):c.5672C>T (p.Ala1891Val)

gnomAD frequency: 0.00001  dbSNP: rs397507360

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000758912	SCV000210362	uncertain significance	not provided	2014-05-29	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.5672C>T at the cDNA level, p.Ala1891Val (A1891V) at the protein level, and results in the change of an Alanine to a Valine (GCA>GTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Although the variant creates a new cryptic donor site, the probability of it being used is significantly lower than the natural donor site; thus, the cryptic site is unlikely to have a deleterious effect on the protein. BRCA2 Ala1891Val was not 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 Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Ala1891Val occurs at a position that is highly variable across species and is not located in a known functional domain. In addition, 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 Ala1891Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000460706	SCV000549738	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-09-25	criteria provided, single submitter	clinical testing	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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1891 of the BRCA2 protein (p.Ala1891Val). This variant is present in population databases (rs397507360, gnomAD 0.003%). 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: 37987). 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.
Ambry Genetics	RCV000562290	SCV000665959	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-16	criteria provided, single submitter	clinical testing	The p.A1891V variant (also known as c.5672C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 5672. The alanine at codon 1891 is replaced by valine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758912	SCV000887855	uncertain significance	not provided	2018-08-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000562290	SCV001341636	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-13	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 1891 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 reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 30982232).. This variant has been identified in 3/250216 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.
Fulgent Genetics, Fulgent Genetics	RCV002477036	SCV002784618	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2021-09-23	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000562290	SCV003849001	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	RCV000031568	SCV004846620	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 1891 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/250216 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.
Breakthrough Genomics, Breakthrough Genomics	RCV000758912	SCV005192111	uncertain significance	not provided		criteria provided, single submitter	not provided
Sharing Clinical Reports Project (SCRP)	RCV000031568	SCV000054173	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2009-12-14	no assertion criteria provided	clinical testing