NM_000059.4(BRCA2):c.3540G>C (p.Lys1180Asn) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Oct 3, 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:: RCV000220199.12

Allele description [Variation Report for NM_000059.4(BRCA2):c.3540G>C (p.Lys1180Asn)]

NM_000059.4(BRCA2):c.3540G>C (p.Lys1180Asn)

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.3540G>C (p.Lys1180Asn)

HGVS:

NC_000013.11:g.32337895G>C
NG_012772.3:g.27416G>C
NM_000059.4:c.3540G>CMANE SELECT
NP_000050.2:p.Lys1180Asn
NP_000050.3:p.Lys1180Asn
LRG_293t1:c.3540G>C
LRG_293:g.27416G>C
LRG_293p1:p.Lys1180Asn
NC_000013.10:g.32912032G>C
NM_000059.3:c.3540G>C

Protein change:

K1180N

Links:

dbSNP: rs864622363

NCBI 1000 Genomes Browser:

rs864622363

Molecular consequence:

NM_000059.4:c.3540G>C - 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
SCV000277301	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Oct 3, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30093976, 32101877 Citation Link,
SCV000688814	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 14, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003846690	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

SCV000277301

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Oct 3, 2023)

germline

clinical testing

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

Citation Link,

SCV000688814

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 14, 2019)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003846690

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

Clinical genetic testing outcome with multi-gene panel in Asian patients with multiple primary cancers.

Chan GHJ, Ong PY, Low JJH, Kong HL, Ow SGW, Tan DSP, Lim YW, Lim SE, Lee SC.

Oncotarget. 2018 Jul 17;9(55):30649-30660. doi: 10.18632/oncotarget.25769.

PubMed [citation]

PMID:: 30093976
PMCID:: PMC6078133

Frequency of BRCA1 and BRCA2 Mutations in Individuals with Breast and Ovarian Cancer in a Chinese Hakka Population Using Next-Generation Sequencing.

Wu H, Wang Q, Guo X, Liu Q, Zhang Q, Huang Q, Yu Z.

Hum Hered. 2019;84(4-5):160-169. doi: 10.1159/000505268. Epub 2020 Feb 26.

PubMed [citation]

PMID:: 32101877

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000277301.5

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

Description

The p.K1180N variant (also known as c.3540G>C), located in coding exon 10 of the BRCA2 gene, results from a G to C substitution at nucleotide position 3540. The lysine at codon 1180 is replaced by asparagine, an amino acid with similar properties. This alteration has been reported as a variant of unknown significance in an individual with a personal history of ovarian cancer from a cohort of 1191 cancer index patients who underwent clinical evaluation and testing with multigene panels (Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660). In another study, this alteration was detected in a patient diagnosed with breast cancer at age 51 (Wu H et al. Hum Hered, 2019 Feb;84:160-169). 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

From Color Diagnostics, LLC DBA Color Health, SCV000688814.3

#	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

From University of Washington Department of Laboratory Medicine, University of Washington, SCV003846690.1

#	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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