NM_000059.4(BRCA2):c.8593T>G (p.Leu2865Val) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Dec 21, 2021
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:: RCV000574991.17

Allele description [Variation Report for NM_000059.4(BRCA2):c.8593T>G (p.Leu2865Val)]

NM_000059.4(BRCA2):c.8593T>G (p.Leu2865Val)

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.8593T>G (p.Leu2865Val)

HGVS:

NC_000013.11:g.32371061T>G
NG_012772.3:g.60582T>G
NM_000059.4:c.8593T>GMANE SELECT
NP_000050.2:p.Leu2865Val
NP_000050.3:p.Leu2865Val
LRG_293t1:c.8593T>G
LRG_293:g.60582T>G
LRG_293p1:p.Leu2865Val
NC_000013.10:g.32945198T>G
NM_000059.3:c.8593T>G
U43746.1:n.8821T>G

Protein change:

L2865V

Links:

dbSNP: rs80359117

NCBI 1000 Genomes Browser:

rs80359117

Molecular consequence:

NM_000059.4:c.8593T>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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Mus musculus RIKEN cDNA 1110005A23 gene, mRNA (cDNA clone IMAGE:30550736), with ...
Mus musculus RIKEN cDNA 1110005A23 gene, mRNA (cDNA clone IMAGE:30550736), with apparent retained intron
gi|62948050|gb|BC094393.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000661165	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Mar 4, 2020)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 18451181, 19043619, 23108138, 29394989, 29884841 Citation Link,
SCV001736054	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 21, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 18451181, 23108138, 29884841, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000661165

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Mar 4, 2020)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV001736054

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 21, 2021)

germline

clinical testing

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

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

Classifying Variants of Undetermined Significance in BRCA2 with protein likelihood ratios.

Karchin R, Agarwal M, Sali A, Couch F, Beattie MS.

Cancer Inform. 2008;6:203-16. Epub 2008 Apr 18.

PubMed [citation]

PMID:: 19043619
PMCID:: PMC2587343

Assessment of the Clinical Relevance of BRCA2 Missense Variants by Functional and Computational Approaches.

Guidugli L, Shimelis H, Masica DL, Pankratz VS, Lipton GB, Singh N, Hu C, Monteiro ANA, Lindor NM, Goldgar DE, Karchin R, Iversen ES, Couch FJ.

Am J Hum Genet. 2018 Feb 1;102(2):233-248. doi: 10.1016/j.ajhg.2017.12.013. Epub 2018 Jan 25.

PubMed [citation]

PMID:: 29394989
PMCID:: PMC5985401

See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV000661165.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV001736054.2

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

Description

This missense variant replaces leucine with valine at codon 2865 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that the mutant protein exhibits normal homologous DNA repair activity (PMID: 18451181, 23108138, 29884841). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. 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 16, 2024

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