NM_000059.4(BRCA2):c.4117A>G (p.Met1373Val) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jun 1, 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:: RCV003157537.6

Allele description [Variation Report for NM_000059.4(BRCA2):c.4117A>G (p.Met1373Val)]

NM_000059.4(BRCA2):c.4117A>G (p.Met1373Val)

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.4117A>G (p.Met1373Val)

HGVS:

NC_000013.11:g.32338472A>G
NG_012772.3:g.27993A>G
NM_000059.4:c.4117A>GMANE SELECT
NP_000050.2:p.Met1373Val
NP_000050.3:p.Met1373Val
LRG_293t1:c.4117A>G
LRG_293:g.27993A>G
LRG_293p1:p.Met1373Val
NC_000013.10:g.32912609A>G
NM_000059.3:c.4117A>G

Protein change:

M1373V

Links:

dbSNP: rs781119815

NCBI 1000 Genomes Browser:

rs781119815

Molecular consequence:

NM_000059.4:c.4117A>G - 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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AAB30728 (0)
MeSH
prion protein [Rattus norvegicus]
prion protein [Rattus norvegicus]
gi|9653968|gb|AAB30728.2||bbm|33747 |146447

Protein
RecName: Full=Autolysin; AltName: Full=Gamete lytic enzyme; Short=GLE; AltName: ...
RecName: Full=Autolysin; AltName: Full=Gamete lytic enzyme; Short=GLE; AltName: Full=Gametolysin; Flags: Precursor
gi|399543|sp|P31178.1|GLE_CHLRE

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003848694	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]
SCV004005519	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jun 1, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003848694

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]

SCV004005519

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jun 1, 2023)

germline

clinical testing

Citation Link

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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 University of Washington Department of Laboratory Medicine, University of Washington, SCV003848694.1

#	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

From Ambry Genetics, SCV004005519.2

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

Description

The p.M1373V variant (also known as c.4117A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 4117. The methionine at codon 1373 is replaced by valine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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

Last Updated: Sep 29, 2024

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