NM_000059.4(BRCA2):c.5590G>A (p.Asp1864Asn) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 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:: RCV000129542.15

Allele description [Variation Report for NM_000059.4(BRCA2):c.5590G>A (p.Asp1864Asn)]

NM_000059.4(BRCA2):c.5590G>A (p.Asp1864Asn)

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.5590G>A (p.Asp1864Asn)

HGVS:

NC_000013.11:g.32339945G>A
NG_012772.3:g.29466G>A
NM_000059.4:c.5590G>AMANE SELECT
NP_000050.2:p.Asp1864Asn
NP_000050.3:p.Asp1864Asn
LRG_293t1:c.5590G>A
LRG_293:g.29466G>A
LRG_293p1:p.Asp1864Asn
NC_000013.10:g.32914082G>A
NM_000059.3:c.5590G>A
p.D1864N

Protein change:

D1864N

Links:

dbSNP: rs587781536

NCBI 1000 Genomes Browser:

rs587781536

Molecular consequence:

NM_000059.4:c.5590G>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
SCV000184322	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Apr 8, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26852015, 27257965, 31161121, 31428572 Citation Link,
SCV000906111	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 14, 2022)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 22126563, 26852015, 27257965, 28111427, 30725392, 31161121, 31428572, 33078592, 33471991, 35402282, 25741868
SCV003848933	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

SCV000184322

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Apr 8, 2022)

germline

clinical testing

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

Citation Link,

SCV000906111

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 14, 2022)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

SCV003848933

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

Frequent germline mutation in the BRCA2 gene in esophageal squamous cell carcinoma patients from a low-risk Chinese population.

Zhong L, Zhu ZZ, Shen Y, Sun G, Zhao X, Zhang S, Yin X, Zhu J, Xu Z, Zhu G.

Asian Pac J Cancer Prev. 2011;12(7):1771-6.

PubMed [citation]

PMID:: 22126563

Novel germline mutations and unclassified variants of BRCA1 and BRCA2 genes in Chinese women with familial breast/ovarian cancer.

Cao WM, Gao Y, Yang HJ, Xie SN, Ding XW, Pan ZW, Ye WW, Wang XJ.

BMC Cancer. 2016 Feb 6;16:64. doi: 10.1186/s12885-016-2107-6.

PubMed [citation]

PMID:: 26852015
PMCID:: PMC4744435

See all PubMed Citations (12)

Details of each submission

From Ambry Genetics, SCV000184322.8

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

Description

The p.D1864N variant (also known as c.5590G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 5590. The aspartic acid at codon 1864 is replaced by asparagine, an amino acid with highly similar properties. This alteration was identified in a 66-year-old Chinese male diagnosed with with esophageal squamous cell carcinoma who had no family history of cancer but did have a personal history of tobacco use (Zhong L et al. Asian Pac. J. Cancer Prev. 2011;12:1771-6). This alteration was also identified in multiple individuals diagnosed with breast and/or ovarian cancer (Cao WM et al. BMC Cancer. 2016 Feb;16:64; Zhong X et al. PLoS ONE. 2016 Jun;11:e0156789; Kim HN et al. Chonnam Med J, 2019 May;55:99-103; Zhunussova G et al. Front Oncol, 2019 Aug;9:673). 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 Color Diagnostics, LLC DBA Color Health, SCV000906111.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This missense variant replaces aspartic acid with asparagine at codon 1864 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 multiple individuals affected with breast or ovarian cancer (PMID: 26852015, 27257965, 28111427, 30725392, 31161121, 33078592, 35402282), an individual affected with esophageal cancer (PMID: 22126563), and two individuals affected with colorectal cancer (PMID: 31428572). In a large breast cancer case-control meta analysis, this variant was reported in 3/60466 cases and 2/53461 unaffected controls; (OR=1.326 (95%CI 0.222 to 7.938); Leiden Open Variation Database DB-ID BRCA2_006877 (PMID: 33471991)). This variant has been identified in 3/246000 chromosomes 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

From University of Washington Department of Laboratory Medicine, University of Washington, SCV003848933.1

#	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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