NM_000059.4(BRCA2):c.6347A>T (p.His2116Leu) 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:: RCV000219720.13

Allele description [Variation Report for NM_000059.4(BRCA2):c.6347A>T (p.His2116Leu)]

NM_000059.4(BRCA2):c.6347A>T (p.His2116Leu)

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.6347A>T (p.His2116Leu)

HGVS:

NC_000013.11:g.32340702A>T
NG_012772.3:g.30223A>T
NM_000059.4:c.6347A>TMANE SELECT
NP_000050.2:p.His2116Leu
NP_000050.3:p.His2116Leu
LRG_293t1:c.6347A>T
LRG_293:g.30223A>T
LRG_293p1:p.His2116Leu
NC_000013.10:g.32914839A>T
NM_000059.3:c.6347A>T

Protein change:

H2116L

Links:

dbSNP: rs55953736

NCBI 1000 Genomes Browser:

rs55953736

Molecular consequence:

NM_000059.4:c.6347A>T - 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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glyceraldehyde-3-phosphate dehydrogenase A, partial [Pectobacterium odoriferum]
glyceraldehyde-3-phosphate dehydrogenase A, partial [Pectobacterium odoriferum]
gi|2168678143|gb|UHJ15676.1|

Protein
Assembly links for BioSample (Select 36038172) (1)
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000276262	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jun 16, 2022)	germline	clinical testing	Citation Link,
SCV000683777	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 19, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003852450	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

SCV000276262

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jun 16, 2022)

germline

clinical testing

Citation Link,

SCV000683777

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Sep 19, 2022)

germline

clinical testing

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

SCV003852450

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

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

Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots".

Dines JN, Shirts BH, Slavin TP, Walsh T, King MC, Fowler DM, Pritchard CC.

Genet Med. 2020 May;22(5):825-830. doi: 10.1038/s41436-019-0740-6. Epub 2020 Jan 8.

PubMed [citation]

PMID:: 31911673
PMCID:: PMC7200594

Details of each submission

From Ambry Genetics, SCV000276262.5

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

Description

The p.H2116L variant (also known as c.6347A>T), located in coding exon 10 of the BRCA2 gene, results from an A to T substitution at nucleotide position 6347. The histidine at codon 2116 is replaced by leucine, an amino acid with similar properties. 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, SCV000683777.4

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

Description

This missense variant replaces histidine with leucine at codon 2116 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 in the Leiden Open-source Variation Database (https://databases.lovd.nl/shared/individuals/00095654). 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

From University of Washington Department of Laboratory Medicine, University of Washington, SCV003852450.1

#	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: Oct 20, 2024

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