NM_000059.4(BRCA2):c.631G>A (p.Val211Ile) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jul 6, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000213157.17

Allele description [Variation Report for NM_000059.4(BRCA2):c.631G>A (p.Val211Ile)]

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

Gene:

BRCA2:BRCA2 DNA repair associated [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q13.1

Genomic location:

Preferred name:

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

HGVS:

NC_000013.11:g.32326613G>A
NG_012772.3:g.16134G>A
NM_000059.4:c.631G>AMANE SELECT
NP_000050.2:p.Val211Ile
NP_000050.3:p.Val211Ile
LRG_293t1:c.631G>A
LRG_293:g.16134G>A
LRG_293p1:p.Val211Ile
NC_000013.10:g.32900750G>A
NM_000059.3:c.631G>A
U43746.1:n.859G>A

Protein change:

V211I

Links:

dbSNP: rs80358871

NCBI 1000 Genomes Browser:

rs80358871

Molecular consequence:

NM_000059.4:c.631G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

Recent activity

Clear Turn Off Turn On

LOW QUALITY PROTEIN: ephrin type-A receptor 8 [Alexandromys fortis]
LOW QUALITY PROTEIN: ephrin type-A receptor 8 [Alexandromys fortis]
gi|2287681251|ref|XP_050009825.1|

Protein

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000275759	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jul 6, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 12960223, 19179552, 19423647, 21523855, 21934105, 22962691, 29446198 Citation Link,
SCV000683772	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 20, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000275759

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jul 6, 2022)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link,

SCV000683772

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 20, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sensitivity of BRCA1/2 mutation testing in 466 breast/ovarian cancer families.

Evans DG, Bulman M, Young K, Gokhale D, Lalloo F.

J Med Genet. 2003 Sep;40(9):e107. No abstract available.

PubMed [citation]

PMID:: 12960223
PMCID:: PMC1735589

Two mutations of BRCA2 gene at exon and splicing site in a woman who underwent oncogenetic counseling.

Pensabene M, Spagnoletti I, Capuano I, Condello C, Pepe S, Contegiacomo A, Lombardi G, Bevilacqua G, Caligo MA.

Ann Oncol. 2009 May;20(5):874-8. doi: 10.1093/annonc/mdn724. Epub 2009 Jan 29.

PubMed [citation]

PMID:: 19179552

See all PubMed Citations (8)

Details of each submission

From Ambry Genetics, SCV000275759.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV000683772.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine