NM_000059.4(BRCA2):c.3910A>G (p.Thr1304Ala) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (3 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:: RCV000417556.17

Allele description [Variation Report for NM_000059.4(BRCA2):c.3910A>G (p.Thr1304Ala)]

NM_000059.4(BRCA2):c.3910A>G (p.Thr1304Ala)

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.3910A>G (p.Thr1304Ala)

HGVS:

NC_000013.11:g.32338265A>G
NG_012772.3:g.27786A>G
NM_000059.4:c.3910A>GMANE SELECT
NP_000050.2:p.Thr1304Ala
NP_000050.3:p.Thr1304Ala
LRG_293t1:c.3910A>G
LRG_293:g.27786A>G
LRG_293p1:p.Thr1304Ala
NC_000013.10:g.32912402A>G
NM_000059.3:c.3910A>G
U43746.1:n.4138A>G
p.T1304A

Nucleotide change:

4138A>G

Protein change:

T1304A

Links:

dbSNP: rs28897723

NCBI 1000 Genomes Browser:

rs28897723

Molecular consequence:

NM_000059.4:c.3910A>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
SCV000515650	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely benign (Dec 8, 2017)	germline	clinical testing	Citation Link,
SCV004021079	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Jun 20, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29360161, 30287823, 29036293 Citation Link,
SCV004024411	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

SCV000515650

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely benign
(Dec 8, 2017)

germline

clinical testing

Citation Link,

SCV004021079

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Jun 20, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV004024411

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	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

Germline mutation prevalence in individuals with pancreatic cancer and a history of previous malignancy.

Dudley B, Karloski E, Monzon FA, Singhi AD, Lincoln SE, Bahary N, Brand RE.

Cancer. 2018 Apr 15;124(8):1691-1700. doi: 10.1002/cncr.31242. Epub 2018 Jan 23.

PubMed [citation]

PMID:: 29360161

Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls.

Momozawa Y, Iwasaki Y, Parsons MT, Kamatani Y, Takahashi A, Tamura C, Katagiri T, Yoshida T, Nakamura S, Sugano K, Miki Y, Hirata M, Matsuda K, Spurdle AB, Kubo M.

Nat Commun. 2018 Oct 4;9(1):4083. doi: 10.1038/s41467-018-06581-8.

PubMed [citation]

PMID:: 30287823
PMCID:: PMC6172276

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000515650.4

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

Description

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

#	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, SCV004021079.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: BRCA2 c.3910A>G (p.Thr1304Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.4e-05 (i.e., 7 heterozygotes) in 208654 control chromosomes (gnomAD v2.1, Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3910A>G has been reported in the literature in individuals affected with pancreatic cancer and cutaneous malignant melanoma (e.g., Goldstein_2017, Dudley_2018), however without strong evidence for causality in both cases. The variant has also been reported in a healthy control (e.g., Momozawa_2018) as well as in 2 carriers in a healthy cohort of women over the age of 70 who have never had cancer (FLOSSIES database). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (VUS, n = 2; Likely benign, n = 5; Benign, n = 1). Based on the evidence outlined above, the variant was classified as VUS-possibly 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, SCV004024411.2

#	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

Last Updated: Oct 20, 2024

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