Submissions for variant NM_000059.4(BRCA2):c.8518A>G (p.Ile2840Val)

gnomAD frequency: 0.00001  dbSNP: rs80359103

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000045543	SCV000073556	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-31	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 2840 of the BRCA2 protein (p.Ile2840Val). This variant is present in population databases (rs80359103, gnomAD 0.002%). This missense change has been observed in individual(s) with BRCA2-related conditions (PMID: 15876480, 16826315, 24916970, 35264596). This variant is also known as 8746A>G. ClinVar contains an entry for this variant (Variation ID: 52609). 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	RCV000132218	SCV000187300	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-22	criteria provided, single submitter	clinical testing	The p.I2840V variant (also known as c.8518A>G), located in coding exon 19 of the BRCA2 gene, results from an A to G substitution at nucleotide position 8518. The isoleucine at codon 2840 is replaced by valine, an amino acid with highly similar properties. This alteration has been detected in a breast cancer family from Spain, which also carried a reported BRCA2 mutation, 8873del4 (Salazar R et al. Cancer Lett. 2006; 233:172-7), and in a breast/ovarian cancer family from Portugal, which also carried a second nearby alteration, p.I2828V, in the BRCA2 gene (Peixoto A et al. Fam Cancer. 2006; 5:379-87). Additionally, this alteration was identified in an individual diagnosed with breast cancer from China (Su Y et al. Front Genet, 2021 Nov;12:674094). In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This amino acid position is not well conserved in available vertebrate species, and valine is the reference amino acid in several 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	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000478553	SCV000600810	uncertain significance	not specified	2021-05-20	criteria provided, single submitter	clinical testing
Mendelics	RCV000045543	SCV000838878	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132218	SCV000902946	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-15	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 2840 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 two individuals affected with breast cancer and one of whom also has a pathogenic BRCA2 co-variant and in a suspected hereditary breast and ovarian cancer family (PMID: 15876480, 16826315, 34917121) This variant also has been detected in a breast cancer case-control meta-analysis in 1/60463 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000339). This variant has been identified in 3/282570 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000478553	SCV000918809	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8518A>G (p.Ile2840Val) results in a conservative amino acid change located in the Tower domain of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251176 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8518A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome, and has also been observed in the control cohorts from multiple studies (examples, Buzolin_2017, Dorling_2021, Guindalini_2022, Karchin_2008, Li_2018, Peixoto_2014, Peixoto_2006, Su_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2:c.8639_8643del(p.Thr2880fs)) (Salazar_2006), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28651617, 33471991, 35264596, 19043619, 30078507, 24916970, 16826315, 15876480, 34917121). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Mendelics	RCV000113953	SCV001139220	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000045543	SCV002819240	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-11-22	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV003137583	SCV003806877	uncertain significance	Malignant tumor of prostate	2022-10-28	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2 supporting, BP4 supporting
Baylor Genetics	RCV003460620	SCV004213718	uncertain significance	Familial cancer of breast	2023-07-31	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113953	SCV000147389	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing