Submissions for variant NM_000059.4(BRCA2):c.5869A>G (p.Ile1957Val)

gnomAD frequency: 0.00004  dbSNP: rs80358817

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000203620	SCV000072793	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1957 of the BRCA2 protein (p.Ile1957Val). This variant is present in population databases (rs80358817, gnomAD 0.004%). This missense change has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 21702907, 27376475, 34326862). ClinVar contains an entry for this variant (Variation ID: 51957). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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	RCV000129497	SCV000184269	likely benign	Hereditary cancer-predisposing syndrome	2021-04-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000044780	SCV000210620	likely benign	not specified	2018-02-19	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Counsyl	RCV000113498	SCV000487780	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-11-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000513016	SCV000608681	uncertain significance	not provided	2017-04-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044780	SCV000694909	uncertain significance	not specified	2019-08-16	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5869A>G (p.Ile1957Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict that this variant may have an impact on normal splicing by creating a 5' cryptic donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 250986 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5869A>G has been reported in the literature, without strong evidence for causality (Schenkel_2016). This report however, does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (2x likely benign and 5x uncertain significance). Based on the evidence outlined above, the variant was classified as uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000044780	SCV000883508	uncertain significance	not specified	2019-06-20	criteria provided, single submitter	clinical testing	The BRCA2 c.5869A>G; p.Ile1957Val variant (rs80358817) has been reported in at least one individual affected with hereditary breast and ovarian cancer (Schenkel 2016). It is reported as a variant of unknown significance by several laboratories in ClinVar (Variation ID: 51957) and observed in the European population at an overall frequency of 0.004% (5/126572) in the Genome Aggregation Database. The isoleucine at codon 1957 and computational algorithms (PolyPhen-2, SIFT) predict that this variant does not affect protein structure and/or function. Splice predictors (Alamut v.2.11) predict that this variant creates a cryptic donor splice site, but functional mRNA studies are necessary to determine the effect of this variant on splicing. Due to limited information regarding this variant, its clinical significance cannot be determined with certainty. References: Schenkel L et al. Clinical Next-Generation Sequencing Pipeline Outperforms a Combined Approach Using Sanger Sequencing and Multiplex Ligation-Dependent Probe Amplification in Targeted Gene Panel Analysis. J Mol Diagn. 2016 Sep;18(5):657-667.
Color Diagnostics, LLC DBA Color Health	RCV000129497	SCV000903087	likely benign	Hereditary cancer-predisposing syndrome	2016-10-11	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000513016	SCV001469444	uncertain significance	not provided	2020-07-19	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129497	SCV003850739	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).
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113498	SCV000146720	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000513016	SCV001551241	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BRCA2 p.Ile1957Val variant was identified in the literature in hereditary breast and ovarian cancer patients, however the frequency of this variant in an affected population was not provided (Schenkel_2016_PMID:27376475; Hondow_2011_PMID:21702907). The variant was identified in dbSNP (ID: rs80358817), ClinVar (classified as likely benign 2x and uncertain significance 7x; associated condition is hereditary breast and ovarian cancer syndrome), and Cosmic (confirmed somatically in a breast carcinoma tissue with a FATHMM prediction score of 0.10, neutral). The variant was identified in control databases in 5 of 282390 chromosomes at a frequency of 0.000018 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European (non-Finnish) population in 5 of 128968 chromosomes (freq: 0.000039), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other or South Asian populations. The p.Ile1957 residue is not 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. The variant occurs outside of the splicing consensus sequence; however three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict the creation of a new 5’ splice site near the site of variation. 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 uncertain significance.