Submissions for variant NM_000059.4(BRCA2):c.2461G>A (p.Val821Ile)

gnomAD frequency: 0.00001  dbSNP: rs756411508

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000564932	SCV000668762	likely benign	Hereditary cancer-predisposing syndrome	2018-10-29	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
CSER _CC_NCGL, University of Washington	RCV000590888	SCV000700126	uncertain significance	Hereditary breast ovarian cancer syndrome	2016-10-01	criteria provided, single submitter	research	Found in a 43 year old female patient having exome sequencing for an unrelated indication. No history of breast or ovarian cancer. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000590888	SCV000836077	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-11-01	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 821 of the BRCA2 protein (p.Val821Ile). This variant is present in population databases (rs756411508, gnomAD 0.006%). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 28111427). ClinVar contains an entry for this variant (Variation ID: 483080). 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.
Color Diagnostics, LLC DBA Color Health	RCV000564932	SCV000906040	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-02	criteria provided, single submitter	clinical testing
GeneDx	RCV001354575	SCV001769547	uncertain significance	not provided	2019-10-28	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in a control subject and in no cases in a breast cancer case/control study (Momozawa 2018); This variant is associated with the following publications: (PMID: 30287823)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000564932	SCV003848339	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354575	SCV001549223	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BRCA2 p.Val821Ile variant was identified in 1 of 1596 proband chromosomes (frequency: 0.0006) from individuals or families with hereditary breast and ovarian cancer and was present in 2 of 24980 control chromosomes (frequency: 0.00008) from healthy individuals (Park 2017, Momozawa 2018). The variant was also identified in dbSNP (ID: rs756411508) as "With Uncertain significance allele", in ClinVar (3x as Uncertain significance by Invitae and two other submitters, 1x as likely benign by Ambry Genetics), LOVD 3.0, and in the UMD-LSDB (2 records of unknown clinical significance) database. It was also identified in control databases in 2 of 242648 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 1 of 111180 chromosomes (freq: 0.000009) and East Asian in 1 of 17926 chromosomes (freq: 0.00006), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, Finnish or South Asian populations. The p.Val821 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 and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume 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 uncertain significance.