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

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Dec 4, 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:: RCV000496306.17

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 breast ovarian cancer syndrome
Synonyms:: Hereditary breast and ovarian cancer syndrome; Hereditary breast and ovarian cancer; Hereditary breast and ovarian cancer syndrome (HBOC); See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0003582; MeSH: D061325; MedGen: C0677776; Orphanet: 145

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cofilin-1 [Alexandromys fortis]
cofilin-1 [Alexandromys fortis]
gi|2287694109|ref|XP_049993772.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000587558	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto - The Canadian Open Genetics Repository (COGR)	no assertion criteria provided	Pathogenic (Jan 31, 2014)	germline	research
SCV000694962	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 17, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 22009639, 23451180, 12960223, 22962691, 19542536, 19179552, 19423647, 27062684, 27125725 Citation Link,
SCV000838740	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (Jul 2, 2018)	unknown	clinical testing	Citation Link,
SCV001577033	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 4, 2023)	germline	clinical testing	PubMed (14) [See all records that cite these PMIDs] 19423647, 21934105, 27125725, 30613976, 31336956, 32438681, 32853339, 33804961, 17576681, 9536098, 19179552, 22962691, 23451180, 28492532

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Summary from all submissions

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

Citations

PubMed

Predictive factors for BRCA1/BRCA2 mutations in women with ductal carcinoma in situ.

Bayraktar S, Elsayegh N, Gutierrez Barrera AM, Lin H, Kuerer H, Tasbas T, Muse KI, Ready K, Litton J, Meric-Bernstam F, Hortobagyi GN, Albarracin CT, Arun B.

Cancer. 2012 Mar 15;118(6):1515-22. doi: 10.1002/cncr.26428. Epub 2011 Aug 25. Erratum in: Cancer. 2014 Mar 15;120(6):927.

PubMed [citation]

PMID:: 22009639
PMCID:: PMC4407692

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

See all PubMed Citations (18)

Details of each submission

From Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto - The Canadian Open Genetics Repository (COGR), SCV000587558.1

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

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000694962.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

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.

#	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 Mendelics, SCV000838740.2

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

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001577033.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

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.

#	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

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