NM_000059.4(BRCA2):c.4313T>C (p.Val1438Ala) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Mar 23, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV002331986.6

Allele description [Variation Report for NM_000059.4(BRCA2):c.4313T>C (p.Val1438Ala)]

NM_000059.4(BRCA2):c.4313T>C (p.Val1438Ala)

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.4313T>C (p.Val1438Ala)

HGVS:

NC_000013.11:g.32338668T>C
NG_012772.3:g.28189T>C
NM_000059.4:c.4313T>CMANE SELECT
NM_001406719.1:c.4313T>C
NM_001406720.1:c.4313T>C
NP_000050.2:p.Val1438Ala
NP_000050.3:p.Val1438Ala
NP_001393648.1:p.Val1438Ala
NP_001393649.1:p.Val1438Ala
LRG_293t1:c.4313T>C
LRG_293:g.28189T>C
LRG_293p1:p.Val1438Ala
NC_000013.10:g.32912805T>C
NM_000059.3:c.4313T>C
NR_176251.1:n.4512T>C

Protein change:

V1438A

Molecular consequence:

NM_000059.4:c.4313T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406719.1:c.4313T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406720.1:c.4313T>C - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002626800	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Oct 16, 2019)	germline	clinical testing	Citation Link,
SCV003850408	University of Washington Department of Laboratory Medicine, University of Washington	criteria provided, single submitter (Dines et al. (Genet Med. 2020))	Likely benign (Mar 23, 2023)	germline	curation	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002626800

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Oct 16, 2019)

germline

clinical testing

Citation Link,

SCV003850408

University of Washington Department of Laboratory Medicine, University of Washington

criteria provided, single submitter

(Dines et al. (Genet Med. 2020))

Likely benign
(Mar 23, 2023)

germline

curation

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, curation

Citations

PubMed

Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots".

Dines JN, Shirts BH, Slavin TP, Walsh T, King MC, Fowler DM, Pritchard CC.

Genet Med. 2020 May;22(5):825-830. doi: 10.1038/s41436-019-0740-6. Epub 2020 Jan 8.

PubMed [citation]

PMID:: 31911673
PMCID:: PMC7200594

Details of each submission

From Ambry Genetics, SCV002626800.2

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

Description

The p.V1438A variant (also known as c.4313T>C), located in coding exon 10 of the BRCA2 gene, results from a T to C substitution at nucleotide position 4313. The valine at codon 1438 is replaced by alanine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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 University of Washington Department of Laboratory Medicine, University of Washington, SCV003850408.1

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

Description

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).

#	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 1, 2024

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