NM_000059.4(BRCA2):c.9821T>G (p.Leu3274Trp) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 19, 2024
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:: RCV000131538.10

Allele description [Variation Report for NM_000059.4(BRCA2):c.9821T>G (p.Leu3274Trp)]

NM_000059.4(BRCA2):c.9821T>G (p.Leu3274Trp)

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.9821T>G (p.Leu3274Trp)

HGVS:

NC_000013.11:g.32398334T>G
NG_012772.3:g.87855T>G
NM_000059.4:c.9821T>GMANE SELECT
NP_000050.2:p.Leu3274Trp
NP_000050.3:p.Leu3274Trp
LRG_293t1:c.9821T>G
LRG_293:g.87855T>G
LRG_293p1:p.Leu3274Trp
NC_000013.10:g.32972471T>G
NM_000059.3:c.9821T>G
p.L3274W

Nucleotide change:

10049T>G

Protein change:

L3274W

Links:

dbSNP: rs431825380

NCBI 1000 Genomes Browser:

rs431825380

Molecular consequence:

NM_000059.4:c.9821T>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000186533	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jan 19, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 24249303, 24504028, 28767289, 29176636 Citation Link,
SCV000906825	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 14, 2020)	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

SCV000186533

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jan 19, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV000906825

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jul 14, 2020)

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

Prevalence and differentiation of hereditary breast and ovarian cancers in Japan.

Nakamura S, Takahashi M, Tozaki M, Nakayama T, Nomizu T, Miki Y, Murakami Y, Aoki D, Iwase T, Nishimura S, Yamauchi H, Ohsumi S, Baba S, Shimizu T.

Breast Cancer. 2015 Sep;22(5):462-8. doi: 10.1007/s12282-013-0503-1. Epub 2013 Nov 19.

PubMed [citation]

PMID:: 24249303

Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status.

Cunningham JM, Cicek MS, Larson NB, Davila J, Wang C, Larson MC, Song H, Dicks EM, Harrington P, Wick M, Winterhoff BJ, Hamidi H, Konecny GE, Chien J, Bibikova M, Fan JB, Kalli KR, Lindor NM, Fridley BL, Pharoah PP, Goode EL.

Sci Rep. 2014 Feb 7;4:4026. doi: 10.1038/srep04026.

PubMed [citation]

PMID:: 24504028
PMCID:: PMC4168524

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000186533.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The p.L3274W variant (also known as c.9821T>G), located in coding exon 26 of the BRCA2 gene, results from a T to G substitution at nucleotide position 9821. The leucine at codon 3274 is replaced by tryptophan, an amino acid with similar properties. This alteration has been reported in 1/260 Japanese high risk breast/ovarian probands (Nakamura S et al. Breast Cancer 2015 Sep; 22(5):462-8), 1/830 Japanese patients who underwent BRCA1/2 testing (Arai M et al. J. Hum. Genet., 2018 Apr;63:447-457), as a germline variant in a cohort of 1063 HDR deficient epithelial ovarian cancers (Cunningham JM et al. Sci Rep, 2014 Feb;4:4026), and in a patient with duodenal adenocarcinoma from a cohort of 854 patients with pancreatic ductal adenocarcinoma, 288 patients with other pancreatic and periampullary neoplasms, and 51 patients with nonneoplastic diseases who underwent pancreatic resection (Shindo K et al. J. Clin. Oncol., 2017 Oct;35:3382-3390). This amino acid position is highly 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 Color Diagnostics, LLC DBA Color Health, SCV000906825.3

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

Description

This missense variant replaces leucine with tryptophan at codon 3274 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual each affected with ovarian cancer (PMID: 24504028) and pancreatic cancer with family history of breast cancer (PMID: 28767289). This variant also has been reported in a family affected with breast/ovarian cancer (PMID: 24249303). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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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