NM_000059.4(BRCA2):c.3420T>A (p.Ser1140Arg) 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:: RCV002451525.6

Allele description [Variation Report for NM_000059.4(BRCA2):c.3420T>A (p.Ser1140Arg)]

NM_000059.4(BRCA2):c.3420T>A (p.Ser1140Arg)

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.3420T>A (p.Ser1140Arg)

HGVS:

NC_000013.11:g.32337775T>A
NG_012772.3:g.27296T>A
NM_000059.4:c.3420T>AMANE SELECT
NP_000050.3:p.Ser1140Arg
LRG_293t1:c.3420T>A
LRG_293:g.27296T>A
NC_000013.10:g.32911912T>A
NM_000059.3:c.3420T>A

Protein change:

S1140R

Links:

dbSNP: rs118093942

NCBI 1000 Genomes Browser:

rs118093942

Molecular consequence:

NM_000059.4:c.3420T>A - 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
SCV002614471	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Apr 27, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29176636, 30287823 Citation Link,
SCV003851948	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

SCV002614471

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Apr 27, 2021)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV003851948

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

Genetic and clinical characteristics in Japanese hereditary breast and ovarian cancer: first report after establishment of HBOC registration system in Japan.

Arai M, Yokoyama S, Watanabe C, Yoshida R, Kita M, Okawa M, Sakurai A, Sekine M, Yotsumoto J, Nomura H, Akama Y, Inuzuka M, Nomizu T, Enomoto T, Nakamura S.

J Hum Genet. 2018 Apr;63(4):447-457. doi: 10.1038/s10038-017-0355-1. Epub 2017 Nov 8. Erratum in: J Hum Genet. 2018 Apr;63(4):541-542. doi: 10.1038/s10038-017-0395-6.

PubMed [citation]

PMID:: 29176636
PMCID:: PMC8716335

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 (3)

Details of each submission

From Ambry Genetics, SCV002614471.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.S1140R variant (also known as c.3420T>A), located in coding exon 10 of the BRCA2 gene, results from a T to A substitution at nucleotide position 3420. The serine at codon 1140 is replaced by arginine, an amino acid with dissimilar properties. This alteration was identified in a Japanese study of individuals who carry BRCA1/2 variants (Arai M et al. J Hum Genet, 2018 Apr;63:447-457). This alteration was also observed with an allele frequency of 0.00014 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00027 in 11,241 female controls of Japanese ancestry. In addition, it was not observed in unselected male breast cancer patients and was observed with an allele frequency of 0.0004 in 12490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This amino acid position is poorly 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

From University of Washington Department of Laboratory Medicine, University of Washington, SCV003851948.1

#	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 29, 2024

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