VCV000052058.26 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(15)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 52058 Accession: VCV000052058.26

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q13.1 13: 32326613 (GRCh38) [ NCBI UCSC ] 13: 32900750 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 1, 2014	May 1, 2024	Dec 4, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000059.4:c.631G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000050.3:p.Val211Ile	missense
NC_000013.11:g.32326613G>A
NC_000013.10:g.32900750G>A
NG_012772.3:g.16134G>A
LRG_293:g.16134G>A
LRG_293t1:c.631G>A	LRG_293p1:p.Val211Ile
U43746.1:n.859G>A

... more HGVS ... less HGVS

Protein change

V211I

Other names

Canonical SPDI

NC_000013.11:32326612:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA023869 dbSNP: rs80358871 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
BRCA2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	18962	19121

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Breast-ovarian cancer, familial, susceptibility to, 2	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Dec 5, 2016	RCV000113917.13
Hereditary cancer-predisposing syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jul 6, 2022	RCV000213157.17
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	May 5, 2023	RCV000214066.15
Hereditary breast ovarian cancer syndrome	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Dec 4, 2023	RCV000496306.17
Breast and/or ovarian cancer	Pathogenic (1)	no assertion criteria provided	-	RCV000735584.9
Familial cancer of breast	Pathogenic (1)	criteria provided, single submitter	Jul 8, 2022	RCV003473372.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Dec 05, 2016)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000677666.2 First in ClinVar: Apr 01, 2014 Last updated: Dec 24, 2022	Publications: PubMed (10) PubMed: 22962691‚ 23451180‚ 22009639‚ 21523855‚ 27125725‚ 19542536‚ 19179552‚ 19423647‚ 12960223‚ 21934105
Pathogenic (Jul 08, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004210543.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (Feb 23, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003810379.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Dec 04, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001577033.4 First in ClinVar: May 10, 2021 Last updated: Feb 20, 2024	Publications: PubMed (13) PubMed: 19179552‚ 19423647‚ 21934105‚ 27125725‚ 30613976‚ 31336956‚ 32438681‚ 32853339‚ 33804961‚ 17576681‚ 9536098‚ 22962691‚ 23451180 Comment: 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). … (more) 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. (less)
Pathogenic (May 20, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000683772.4 First in ClinVar: Feb 19, 2018 Last updated: Jan 08, 2022	Comment: 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 … (more) 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. (less)
Pathogenic (Oct 02, 2015)	criteria provided, single submitter (CIMBA Mutation Classification guidelines May 2016) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: germline	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge Accession: SCV000327389.4 First in ClinVar: Apr 01, 2014 Last updated: Dec 11, 2022
Pathogenic (Jul 02, 2018)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Hereditary breast and ovarian cancer syndrome Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV000838740.2 First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022
Pathogenic (May 05, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000279589.11 First in ClinVar: May 29, 2016 Last updated: May 27, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Aug 17, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000694962.2 First in ClinVar: Aug 07, 2017 Last updated: Oct 04, 2023	Publications: PubMed (9) PubMed: 22009639‚ 23451180‚ 12960223‚ 22962691‚ 19542536‚ 19179552‚ 19423647‚ 27062684‚ 27125725 Comment: 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 … (more) 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. (less)
Pathogenic (Dec 22, 2021)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV004220498.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (21) PubMed: 30883759‚ 27125725‚ 23451180‚ 22962691‚ 19423647‚ 19179552‚ 12960223‚ 21934105‚ 32853339‚ 32854451‚ 32338768‚ 29446198‚ 30613976‚ 31512090‚ 32058061‚ 33287145‚ 21523855‚ 22009639‚ 31336956‚ 32438681‚ 33471991 Comment: 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 … (more) 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. (less)
Pathogenic (Jul 06, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000275759.7 First in ClinVar: May 29, 2016 Last updated: May 01, 2024	Publications: PubMed (7) PubMed: 12960223‚ 19179552‚ 19423647‚ 21523855‚ 21934105‚ 22962691‚ 29446198 Comment: 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 … (more) 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. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Breast and/or ovarian cancer Affected status: unknown Allele origin: germline	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research Study: The Canadian Open Genetics Repository (COGR) Accession: SCV000863722.1 First in ClinVar: Dec 24, 2018 Last updated: Dec 24, 2018
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV000591699.2 First in ClinVar: Aug 07, 2017 Last updated: Apr 13, 2021	Comment: 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, … (more) 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. (less)
Pathogenic (May 29, 2002)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial 2 Affected status: yes Allele origin: germline	Breast Cancer Information Core (BIC) (BRCA2) Accession: SCV000147341.1 First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014	Observation 1: Number of individuals with the variant: 2 Observation 2: Number of individuals with the variant: 1 Ethnicity/Population group: Caucasian Geographic origin: Italy Observation 3: Number of individuals with the variant: 1 Ethnicity/Population group: Central/Eastern European Observation 4: Number of individuals with the variant: 4 Ethnicity/Population group: Western European
Pathogenic (Jan 31, 2014)	no assertion criteria provided Method: research	Hereditary breast ovarian cancer syndrome Affected status: yes Allele origin: germline	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto Study: The Canadian Open Genetics Repository (COGR) Accession: SCV000587558.1 First in ClinVar: Aug 07, 2017 Last updated: Aug 07, 2017
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Comment:

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.

Comment:

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.

Comment:

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)

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Rare Germline Pathogenic Variants Identified by Multigene Panel Testing and the Risk of Aggressive Prostate Cancer.	Nguyen-Dumont T	Cancers	2021	PMID: 33804961
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.	Breast Cancer Association Consortium	The New England journal of medicine	2021	PMID: 33471991
Germline Sequencing DNA Repair Genes in 5545 Men With Aggressive and Nonaggressive Prostate Cancer.	Darst BF	Journal of the National Cancer Institute	2021	PMID: 32853339
Five Italian Families with Two Mutations in BRCA Genes.	Vietri MT	Genes	2020	PMID: 33287145
Detection of Germline Mutations in a Cohort of 139 Patients with Bilateral Breast Cancer by Multi-Gene Panel Testing: Impact of Pathogenic Variants in Other Genes beyond BRCA1/2.	Fanale D	Cancers	2020	PMID: 32854451
Spectrum of Germline BRCA1 and BRCA2 Variants Identified in 2351 Ovarian and Breast Cancer Patients Referring to a Reference Cancer Hospital of Rome.	Santonocito C	Cancers	2020	PMID: 32438681
Rare germline genetic variants and risk of aggressive prostate cancer.	Nguyen-Dumont T	International journal of cancer	2020	PMID: 32338768
BRCA and PALB2 mutations in a cohort of male breast cancer with one bilateral case.	Vietri MT	European journal of medical genetics	2020	PMID: 32058061
Germline investigation in male breast cancer of DNA repair genes by next-generation sequencing.	Scarpitta R	Breast cancer research and treatment	2019	PMID: 31512090
BRCA1 and BRCA2 Testing through Next Generation Sequencing in a Small Cohort of Italian Breast/Ovarian Cancer Patients: Novel Pathogenic and Unknown Clinical Significance Variants.	Concolino P	International journal of molecular sciences	2019	PMID: 31336956
Mis-splicing in breast cancer: identification of pathogenic BRCA2 variants by systematic minigene assays.	Fraile-Bethencourt E	The Journal of pathology	2019	PMID: 30883759
Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy.	Rizzolo P	International journal of cancer	2019	PMID: 30613976
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.	Rebbeck TR	Human mutation	2018	PMID: 29446198
Multidisciplinary team for elucidation of any new mutation and how this approach can be useful to individualize any genetic result: the case of BRCA2 c.631G>A/c.7008-2A>T genotype Response to: Nagy PL, Mansukhani M. The role of clinical genomic testing in diagnosis and discovery of pathogenic mutations. Expert Rev Mol Diagn 2015;15(9):1101-5.	Minucci A	Expert review of molecular diagnostics	2016	PMID: 27125725
Mutation detection rates associated with specific selection criteria for BRCA1/2 testing in 1854 high-risk families: A monocentric Italian study.	Azzollini J	European journal of internal medicine	2016	PMID: 27062684
Comparative in vitro and in silico analyses of variants in splicing regions of BRCA1 and BRCA2 genes and characterization of novel pathogenic mutations.	Colombo M	PloS one	2013	PMID: 23451180
Multiple sequence variants of BRCA2 exon 7 alter splicing regulation.	Gaildrat P	Journal of medical genetics	2012	PMID: 22962691
Predictive factors for BRCA1/BRCA2 mutations in women with ductal carcinoma in situ.	Bayraktar S	Cancer	2012	PMID: 22009639
An emerging entity: pancreatic adenocarcinoma associated with a known BRCA mutation: clinical descriptors, treatment implications, and future directions.	Lowery MA	The oncologist	2011	PMID: 21934105
Comprehensive prediction of mRNA splicing effects of BRCA1 and BRCA2 variants.	Mucaki EJ	Human mutation	2011	PMID: 21523855
BRCA2 splice site mutations in an Italian breast/ovarian cancer family.	Díez O	Annals of oncology : official journal of the European Society for Medical Oncology	2009	PMID: 19542536
An unusual BRCA2 allele carrying two splice site mutations.	Colombo M	Annals of oncology : official journal of the European Society for Medical Oncology	2009	PMID: 19423647
Two mutations of BRCA2 gene at exon and splicing site in a woman who underwent oncogenetic counseling.	Pensabene M	Annals of oncology : official journal of the European Society for Medical Oncology	2009	PMID: 19179552
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.	Buratti E	Nucleic acids research	2007	PMID: 17576681
Sensitivity of BRCA1/2 mutation testing in 466 breast/ovarian cancer families.	Evans DG	Journal of medical genetics	2003	PMID: 12960223
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098
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Text-mined citations for rs80358871 ...

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Record last updated Oct 27, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs80358871 ...