Submissions for variant NM_000059.4(BRCA2):c.5428G>A (p.Val1810Ile)

gnomAD frequency: 0.00002  dbSNP: rs80358766

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000044658	SCV000072671	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-02-01	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 1810 of the BRCA2 protein (p.Val1810Ile). This variant is present in population databases (rs80358766, gnomAD 0.007%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 32380732, 34178674). ClinVar contains an entry for this variant (Variation ID: 51860). 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	RCV000214539	SCV000274978	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-19	criteria provided, single submitter	clinical testing	The p.V1810I variant (also known as c.5428G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 5428. The valine at codon 1810 is replaced by isoleucine, an amino acid with highly similar properties. This alteration was observed in with an allele frequency of 0.0000 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00009 in 11,241 female controls of Japanese ancestry. In addition, it was not observed in unselected male breast cancer patients and was observed with an allele frequency of 0.0002 in 12490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This alteration was also identified in an individual diagnosed with breast and/or ovarian cancer (Santonocito C et al. Cancers (Basel), 2020 May;12:). This amino acid position is not well 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.
GeneDx	RCV000589093	SCV000279387	uncertain significance	not provided	2022-05-03	criteria provided, single submitter	clinical testing	Observed in individuals with breast or ovarian cancer, but also found in cancer-free controls (Momozawa 2018, Santonocito 2020, Fanale 2021); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5656G>A; This variant is associated with the following publications: (PMID: 25583476, 25079317, 34178674, 30287823, 32438681, 35452513)
Counsyl	RCV000077352	SCV000488153	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-02-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000219100	SCV000694869	uncertain significance	not specified	2023-02-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5428G>A (p.Val1810Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.3e-05 in 298646 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5428G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome, without strong evidence of causality (Chen_2015, Fanale_2021, Incorvaia_2020, Patruno_2021, Santonocito_2020, etc). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been reported (BRCA2 c.5073dup, p.Trp1692MetfsX3; BRCA1 c.1961_1962insA, p.Lys654fs; BRCA1 c.4986+6T>C), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Six submitters classified the variant as VUS while one classified as likely benign. Based on the evidence outlined above, the variant was classified as VUS - possibly benign.
PreventionGenetics, part of Exact Sciences	RCV000589093	SCV000805724	uncertain significance	not provided	2017-02-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000214539	SCV000906816	likely benign	Hereditary cancer-predisposing syndrome	2022-03-30	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589093	SCV002774481	uncertain significance	not provided	2023-02-14	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000016 (4/251184 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast and/or ovarian cancer as well as unaffected controls (PMIDs: 30287823 (2018), 32438681 (2020), 34178674 (2021), and 33471991 (2021)). The variant has also been detected in at least one individual with gastric cancer (PMID: 25583476 (2015)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000214539	SCV003847238	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).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492356	SCV004240327	uncertain significance	Breast and/or ovarian cancer	2022-11-23	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077352	SCV000109149	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-07-06	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077352	SCV000146613	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353798	SCV000591967	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Val1810Ile variant was identified in the literature in an individual with gastric cancer (Chen 2015). The variant was also identified in dbSNP (ID: rs80358766) “With uncertain significance allele”, Clinvitae database (with uncertain significance), COSMIC (in a stomach adenocarcinoma), the ClinVar database (with uncertain significance by BIC, and classification not provided by Invitae) and the BIC database (4x with unknown clinical importance).The variant was also identified in the 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002), the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 2 of 121162 chromosomes (frequency: 0.0000165). The p.Val1810 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.
Genetic Services Laboratory, University of Chicago	RCV000219100	SCV003839281	uncertain significance	not specified	2022-11-28	no assertion criteria provided	clinical testing	DNA sequence analysis of the BRCA2 gene demonstrated a sequence change, c.5428G>A, in exon 11 that results in an amino acid change, p.Val1810Ile. This sequence change has been identified as a variant of uncertain significance in multiple individuals with breast cancer (PMID: 30287823, 34178674, 32438681). This sequence change has been described in the gnomAD database with a frequency of 0.0016% in the overall population (dbSNP rs80358766). The p.Val1810Ile change affects a moderately conserved amino acid residue located in a domain of the BRCA2 protein that is known to be functional. The p.Val1810Ile substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Val1810Ile change remains unknown at this time.
Department of Medical and Surgical Sciences, University of Bologna	RCV000077352	SCV004228410	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)
GenomeConnect - Invitae Patient Insights Network	RCV003483453	SCV004228608	not provided	BRCA2-Related Disorders		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 09-12-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.