NM_000059.4(BRCA2):c.3715A>G (p.Lys1239Glu) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Aug 15, 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:: RCV000160068.9

Allele description [Variation Report for NM_000059.4(BRCA2):c.3715A>G (p.Lys1239Glu)]

NM_000059.4(BRCA2):c.3715A>G (p.Lys1239Glu)

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.3715A>G (p.Lys1239Glu)

Other names:

p.K1239E:AAA>GAA

HGVS:

NC_000013.11:g.32338070A>G
NG_012772.3:g.27591A>G
NM_000059.4:c.3715A>GMANE SELECT
NP_000050.2:p.Lys1239Glu
NP_000050.3:p.Lys1239Glu
LRG_293t1:c.3715A>G
LRG_293:g.27591A>G
LRG_293p1:p.Lys1239Glu
NC_000013.10:g.32912207A>G
NM_000059.3:c.3715A>G

Nucleotide change:

3943A>G

Protein change:

K1239E

Links:

dbSNP: rs374191973

NCBI 1000 Genomes Browser:

rs374191973

Molecular consequence:

NM_000059.4:c.3715A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001338198	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Feb 28, 2020)	germline	clinical testing	Citation Link,
SCV002761154	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 15, 2023)	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

SCV001338198

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Feb 28, 2020)

germline

clinical testing

Citation Link,

SCV002761154

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 15, 2023)

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

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

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001338198.1

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

Description

Variant summary: BRCA2 c.3715A>G (p.Lys1239Glu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 249020 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3715A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=4; VUS, n=1). Based on the evidence outlined above, and in consideration of the prevailing consensus, the variant was classified as likely benign.

#	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 Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV002761154.3

#	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

Last Updated: Sep 29, 2024

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