NM_000059.4(BRCA2):c.631G>A (p.Val211Ile) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: May 5, 2023
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:: RCV000214066.15

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)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000279589	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (May 5, 2023)	germline	clinical testing	Citation Link,
SCV003810379	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 23, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004220498	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Dec 22, 2021)	unknown	clinical testing	PubMed (22) [See all records that cite these PMIDs] 30883759, 27125725, 23451180, 22962691, 19423647, 19179552, 12960223, 21934105, 32853339, 32854451, 32338768, 29446198, 30613976, 31512090, 32058061, 33287145, 21523855, 22009639, 31336956, 32438681, 33471991, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000279589

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(May 5, 2023)

germline

clinical testing

Citation Link,

SCV003810379

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 23, 2022)

germline

clinical testing

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

SCV004220498

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Pathogenic
(Dec 22, 2021)

unknown

clinical testing

PubMed (22)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Mis-splicing in breast cancer: identification of pathogenic BRCA2 variants by systematic minigene assays.

Fraile-Bethencourt E, Valenzuela-Palomo A, Díez-Gómez B, Goina E, Acedo A, Buratti E, Velasco EA.

J Pathol. 2019 Aug;248(4):409-420. doi: 10.1002/path.5268. Epub 2019 Apr 23.

PubMed [citation]

PMID:: 30883759

See all PubMed Citations (23)

Details of each submission

From GeneDx, SCV000279589.11

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

Description

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)

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

From Revvity Omics, Revvity, SCV003810379.2

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

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004220498.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (22)

Description

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.

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

Last Updated: Jun 23, 2024

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