NM_000059.4(BRCA2):c.1951G>T (p.Asp651Tyr) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Jun 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:: RCV000132142.13

Allele description [Variation Report for NM_000059.4(BRCA2):c.1951G>T (p.Asp651Tyr)]

NM_000059.4(BRCA2):c.1951G>T (p.Asp651Tyr)

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.1951G>T (p.Asp651Tyr)

HGVS:

NC_000013.11:g.32336306G>T
NG_012772.3:g.25827G>T
NM_000059.4:c.1951G>TMANE SELECT
NP_000050.2:p.Asp651Tyr
NP_000050.3:p.Asp651Tyr
LRG_293t1:c.1951G>T
LRG_293:g.25827G>T
LRG_293p1:p.Asp651Tyr
NC_000013.10:g.32910443G>T
NM_000059.3:c.1951G>T
U43746.1:n.2179G>T
p.D651Y

Protein change:

D651Y

Links:

dbSNP: rs80358482

NCBI 1000 Genomes Browser:

rs80358482

Molecular consequence:

NM_000059.4:c.1951G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000187213	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Likely benign (Nov 28, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001358925	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 15, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25777348, 25741868
SCV002533283	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Jun 23, 2021)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV003846405	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	1	not provided	not provided	1	not provided	clinical testing, curation

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

BRCA1 and BRCA2 mutations in ethnic Lebanese Arab women with high hereditary risk breast cancer.

El Saghir NS, Zgheib NK, Assi HA, Khoury KE, Bidet Y, Jaber SM, Charara RN, Farhat RA, Kreidieh FY, Decousus S, Romero P, Nemer GM, Salem Z, Shamseddine A, Tfayli A, Abbas J, Jamali F, Seoud M, Armstrong DK, Bignon YJ, Uhrhammer N.

Oncologist. 2015 Apr;20(4):357-64. doi: 10.1634/theoncologist.2014-0364. Epub 2015 Mar 16.

PubMed [citation]

PMID:: 25777348
PMCID:: PMC4391767

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000187213.6

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

Description

This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	1	not provided	not provided		1	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV001358925.3

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

Description

This missense variant replaces aspartic acid with tyrosine at codon 651 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 an individual affected with breast cancer (PMID: 25777348). This variant has been identified in 1/240136 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 Sema4, Sema4, SCV002533283.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	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, SCV003846405.1

#	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: Apr 20, 2024

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