Submissions for variant NM_000059.4(BRCA2):c.235A>G (p.Ile79Val)

gnomAD frequency: 0.00003  dbSNP: rs80358502

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000561580	SCV000668684	likely benign	Hereditary cancer-predisposing syndrome	2016-07-20	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.
Color Diagnostics, LLC DBA Color Health	RCV000561580	SCV000911860	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-21	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 79 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 and detected in a breast cancer case-control meta-analysis in 3/60466 cases and 0/53461 unaffected individuals (PMID: 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_006250). This variant has been identified in 7/282774 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	RCV001588836	SCV001826216	uncertain significance	not provided	2022-12-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 463A>G; This variant is associated with the following publications: (PMID: 28135145, 30287823)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852621	SCV002198857	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-10-07	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 79 of the BRCA2 protein (p.Ile79Val). This variant is present in population databases (rs80358502, gnomAD 0.03%). This missense change has been observed in individual(s) with colorectal cancer and breast cancer (PMID: 28135145, 30287823; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 37783). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
All of Us Research Program, National Institutes of Health	RCV004803011	SCV004846749	uncertain significance	BRCA2-related cancer predisposition	2024-08-30	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 79 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 and detected in a breast cancer case-control meta-analysis in 3/60466 cases and 0/53461 unaffected individuals (PMID: 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_006250). This variant has been identified in 7/282774 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.
Sharing Clinical Reports Project (SCRP)	RCV000031364	SCV000053969	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2008-01-31	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031364	SCV000146419	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000500366	SCV000591666	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Ile79Val variant was not identified in the literature, nor was it identified in the NHLBI Exome Sequencing Project (Exome Variant Server), Fanconi’s Anemia Mutation Database (LOVD), COSMIC, GeneInsight COGR, MutDB or ARUP . This variant was identified in the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 3 of 121174 chromosomes (frequency: 2.05x10-5); all 3 were found in 6614 alleles (frequency: 4.54x10-4) in the European Finnish population, increasing the likelihood that this may be a low frequency benign variant. The variant was not identified in populations of South Asians, European (Non-Finnish), East Asian, African, Latino, and other individuals.The variant was also identified in dbSNP (ID: rs80358502 “With Uncertain significance allele”. The ClinVar database classified the variant as an uncertain significance variant by the Sharing Clinical Reports Project, derived from Myriad reports), as uncertain significance by BIC and classification not provided by Invitae. The variant was identified in BIC database (1x with Unknown clinical importance), and BRCA Share UMD (1x as an unknown variant). The p.Ile79 residue is not conserved in mammals and the variant amino acid Valine (Val) is present in Cows and African clawed frogs, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. The c.235A>G variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict the creation of a cryptic splice acceptor site. 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 although we would lean towards a more benign role for this variant. This variant is classified as a variant of unknown significance.
BRCAlab, Lund University	RCV000031364	SCV004243681	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing