Submissions for variant NM_000059.4(BRCA2):c.631G>A (p.Val211Ile)

dbSNP: rs80358871

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213157	SCV000275759	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-06	criteria provided, single submitter	clinical testing	ONLY INCLUDE IF PT HAS BOTH c.7008-2A>T and p.V211I (c.631G>A) BRCA2 VARIANTS The c.631G>A pathogenic mutation (also known as p.V211I and 859G>A), located in coding exon 6 of the BRCA2 gene, results from a G to A substitution at nucleotide position 631. The amino acid change results in valine to isoleucine at codon 211, an amino acid with highly similar properties; however, this change occurs in the last base pair of coding exon 6, which makes it likely to have some effect on normal mRNA splicing. The c.7008-2A>T (also known as IVS13-2A>T) intronic pathogenic mutation results from an A to T substitution two nucleotides before coding exon 13 in the BRCA2 gene. The c.631G>A and c.7008-2A>T alterations have been identified in cis in multiple individuals and families with HBOC (Gaildrat PJ et al. Med. Genet. 2012 Oct;49(10):609-17; Pensabene M et al. Ann. Oncol. 2009 May;20(5):874-8; Colombo M et al. Ann. Oncol. 2009 Jun;20(6):1143-4). These alterations have also been identified in cis in one individual with pancreatic adenocarcinoma (Lowery MA et al. Oncologist 2011;16(10):1397-402). Functional studies have demonstrated that the c.631G>A alteration leads to the skipping of coding exon 6, leading to a frameshift and alternate stop in coding exon 8 (Ambry internal data; Pensabene M et al. Ann. Oncol. 2009 May;20(5):874-8; Colombo M et al. Ann. Oncol. 2009 Jun;20(6):1143-4). Functional studies have also demonstrated that the c.7008-2A>T alteration leads to multiple transcripts of different lengths, most of which lead to a frameshift and alternate stop codon (Ambry internal data; Pensabene M et al. Ann. Oncol. 2009 May;20(5):874-8; Colombo M et al. Ann. Oncol. 2009 Jun;20(6):1143-4; Houdayer C et al. Hum. Mutat. 2012 Aug;33(8):1228-38; Colombo M et al. PLoS ONE 2013;8(2):e57173). Based on the available evidence, the mutations c.631G>A and c.7008-2A>T are classified as a pathogenic haplotype.
GeneDx	RCV000214066	SCV000279589	pathogenic	not provided	2023-05-05	criteria provided, single submitter	clinical testing	Exonic splice site variant demonstrated to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Pensabene at al., 2009; Colombo et al., 2009; Colombo at al., 2013; Gaildrat et al., 2012; Fraile-Bethencourt et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 859G>A; This variant is associated with the following publications: (PMID: 12960223, 21934105, 19542536, 32438681, 32854451, 19179552, 19423647, 22962691, 27125725, 23983145, 20455026, 31512090, 30883759, 32444794, 31336956, 32380732, 32338768, 33810291, 29446198, 30613976, 33287145, 23451180, 35205366, 35411189, 35264596, 32853339)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000113917	SCV000327389	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000113917	SCV000677666	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-12-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000213157	SCV000683772	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-20	criteria provided, single submitter	clinical testing	This variant alters the last nucleotide of BRCA2 exon 7 from c.G to c.A. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. RNA studies using patient-derived cells (PMID 19179552, 19423647, 23451180) and a mini-gene splicing assay (PMID: 22962691) have demonstrated that this variant causes a complete skipping of exon 7 and premature truncation. This variant has been reported in an individual affected with bilateral breast and ovarian cancer with family history of ovarian cancer and pancreatic cancer in the paternal grandmother and father, respectively (PMID: 27125725). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic. This variant also has been reported to co-occur with c.7008-2A>T in the BRCA2 gene in at least seven unrelated European individuals affected with breast/ovarian cancer (PMID: 19179552, 19423647, 23451180, 27125725, 31336956) and in an individual affected with pancreatic adenocarcinoma (PMID: 21934105). In six of the individuals affected with breast/ovarian cancer, these variants were reported to occur on the same chromosome (in cis phase) determined in part by retro-transcription analysis or segregation analysis in family studies (PMID: 19179552, 19423647, 22962691, 31336956). For several individuals who carried both variants (PMID: 21934105; Color internal data), the phase of the two variants has not been determined. These two variants have not been reported in trans in the literature. Therefore, although this test cannot distinguish if c.631G>A and c.7008-2A>T variants occur on the same chromosome (in cis) or on opposite chromosomes (in trans), it is likely that these variants are in cis when found together in an individual. Medical management should be considered based on the patient's personal and family history.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496306	SCV000694962	pathogenic	Hereditary breast ovarian cancer syndrome	2023-08-17	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.631G>A (p.Val211Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. However, this variant disrupts the last nucleotide of exon 7, and therefore can affect splicing. Several computational tools predict a significant impact on normal splicing: three predict the variant abolishes a 5' splicing donor site and one predicts the variant weakens the same 5' donor site. Several publications report experimental evidence that this variant disrupts mRNA splicing, leading to skipping or shortening of exon 7 (e.g., Pensabene_2009, Colombo_2009, Gaildrat_2012). The variant was absent in 250814 control chromosomes (gnomAD). c.631G>A has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g., Azzollini_2016, Bayraktar_2012, Colombo_2009, Diez_2009, Evans_2003, Gaildrat_2012, Pensabene_2009, Minucci_2016). The variant was reported to co-occur in cis with variant c.7008-2A>T in many (e.g., Azzollini_2016, Colombo_2009, Gaildrat_2012, Pensabene_2009) but not all (e.g., Minucci_2016) of the reported individuals. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 22009639, 23451180, 12960223, 22962691, 19542536, 19179552, 19423647, 27062684, 27125725). Eight submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mendelics	RCV000496306	SCV000838740	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496306	SCV001577033	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-04	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 211 of the BRCA2 protein (p.Val211Ile). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with BRCA2-related cancers. In some cases, this variant occurred on the same chromosome as the c.7008-2A>T variant (PMID: 19179552, 19423647, 21934105, 27125725, 30613976, 31336956, 32438681, 32853339, 33804961). This variant is also known as 859G>A. ClinVar contains an entry for this variant (Variation ID: 52058). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 19179552, 22962691, 23451180; Invitae). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000214066	SCV003810379	pathogenic	not provided	2022-02-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473372	SCV004210543	pathogenic	Familial cancer of breast	2022-07-08	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000214066	SCV004220498	pathogenic	not provided	2021-12-22	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in patients with hereditary breast and ovarian cancer, prostate cancer, male breast cancer, and pancreatic cancer (PMIDs: 33471991 (2021), 32853339 (2021), 32854451 (2020), 32338768 (2020), 32058061 (2020), 32438681 (2020), 33287145 (2020), 30613976 (2019), 31512090 (2019), 31336956 (2019), 27125725 (2016), 22009639 (2012), 21934105 (2011), 19423647 (2009), 19179552 (2009), 12960223 (2003)). In functional studies, this variant has been shown to disrupt splicing and lead to exon skipping and premature truncation of the protein (PMIDs: 30883759 (2019), 23451180 (2013), 22962691 (2012), 19423647 (2009)). Of note, this variant is frequently reported in cis with BRCA2 c.7008-2A>T (p.?), also reported in the literature as IVS13-2A>T (PMIDs: 32338768 (2020), 32058061 (2020), 32438681 (2020), 33287145 (2020), 31336956 (2019), 19423647 (2009), 19179552 (2009), 12960223 (2003)).Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is disease causing or benign. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper BRCA2 mRNA splicing. Based on the available information, this variant is classified as pathogenic.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113917	SCV000147341	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496306	SCV000587558	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000113917	SCV000591699	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing	The p.Val211Ile variant has been previously reported in the literature in 8 of 64 proband chromosomes of individuals with hereditary breast and/or ovarian cancer. However, no control chromosomes were evaluated to establish the prevalence of the variant in the general population (Colombo 2009, Pensabene 2009, Lowery 2011, Gaildrat 2012, Diez 2009). The variant occurs in the last base of the exon and this position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. Indeed, functional studies have shown that the variant altered the natural splice sites leading to exon skipping due to modification of the sequence of the 5' splice site (Pensabene 2009, Gaildrat 2012). The variant has also been reported twice in the UMD database as a variant of unknown significance, and 8 times in the BIC database as a clinically significant variant. In both the cases reported in the UMD database, the variant was found to co-occur with the pathogenic BRCA2 variant (c.7008-2A>T). This other variant is also being reported as co-occurring in this individual. In summary, based on the above information, this variant is classified as pathogenic.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735584	SCV000863722	pathogenic	Breast and/or ovarian cancer		no assertion criteria provided	clinical testing