ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8518A>G (p.Ile2840Val) (rs80359103)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132218 SCV000187300 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000113953 SCV000147389 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Color RCV000132218 SCV000902946 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-25 criteria provided, single submitter clinical testing
GeneDx RCV000657032 SCV000566855 uncertain significance not provided 2017-06-12 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8518A>G at the cDNA level, p.Ile2840Val (I2840V) at the protein level, and results in the change of an Isoleucine to a Valine (ATA>GTA). Using alternate nomenclature, this variant would be defined as BRCA2 8746A>G. This variant has been observed in individuals of Portugese ancestry with a personal and/or family history of breast and/or ovarian cancer, and was reported to co-occur with BRCA2 c.8482A>G (p.Ile2828Val) in at least one individual (Peixoto 2006, Peixoto 2014). Additionally, Salazar et al. (2006) found this variant to co-occur with a BRCA2 frameshift variant, described as pathogenic, in an individual with a personal and/or family history of bilateral breast cancer. BRCA2 Ile2840Val was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Ile2840Val occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is located within the DNA binding domain (Yang 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA2 Ile2840Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000478553 SCV000918809 uncertain significance not specified 2018-01-29 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8518A>G (p.Ile2840Val) located in the Tower domain (via InterPro) results in the alteration of a non-conserved nucleotide and 5/5 in-silico tools predict a benign effect of the variant on protein function. However, these predictions have yet to be functionally assessed. The variant of interest was observed in 3/276902 (allele frequency: 0.000011) control chromosomes (gnomAD), which does not exceed the estimated maximum expected allele frequency for a pathogenic BRCA2 variant of 0.00075. Multiple publications have cited the variant in affected individuals including a reported co-occurrence with another potentially pathogenic BRCA2 variant, c.8645_8648delAACC (p.Lys2882fsX8), providing supporting evidence for a benign role. Multiple clinical diagnostic laboratories performing clinical significance assessments after 2014, classified the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Invitae RCV000045543 SCV000073556 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 2840 of the BRCA2 protein (p.Ile2840Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs80359103, ExAC 0.003%). This variant has been reported in individuals affected with breast cancer (PMID: 16826315, 24916970, 15876480). However, in one of these individuals a pathogenic allele was also identified in BRCA2, which suggests that this c.8518A>G variant was not the primary cause of disease. This variant is also known as 8746A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 52609). The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. In addition, general algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and an algorithm developed specifically for BRCA2 (PMID: 19043619), all suggest that this missense change is likely to be tolerated. These predictions have not been confirmed by published functional studies. 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.
Mendelics RCV000045543 SCV000838878 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000478553 SCV000600810 uncertain significance not specified 2016-11-17 criteria provided, single submitter clinical testing

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