NM_000059.4(BRCA2):c.1343G>A (p.Arg448His) 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:: RCV000130010.15

Allele description [Variation Report for NM_000059.4(BRCA2):c.1343G>A (p.Arg448His)]

NM_000059.4(BRCA2):c.1343G>A (p.Arg448His)

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.1343G>A (p.Arg448His)

HGVS:

NC_000013.11:g.32332821G>A
NG_012772.3:g.22342G>A
NM_000059.4:c.1343G>AMANE SELECT
NP_000050.2:p.Arg448His
NP_000050.3:p.Arg448His
LRG_293t1:c.1343G>A
LRG_293:g.22342G>A
LRG_293p1:p.Arg448His
NC_000013.10:g.32906958G>A
NM_000059.3:c.1343G>A
U43746.1:n.1571G>A
p.R448H

Protein change:

R448H

Links:

dbSNP: rs80358423

NCBI 1000 Genomes Browser:

rs80358423

Molecular consequence:

NM_000059.4:c.1343G>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

Recent activity

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MRPS22 mitochondrial ribosomal protein S22 [Homo sapiens]
MRPS22 mitochondrial ribosomal protein S22 [Homo sapiens]
Gene ID:56945

Gene
Gene Links for GEO Profiles (Select 132511614) (1)
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000184835	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Feb 28, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000911449	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 7, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 15026808, 30287823, 31214711, 32980694, 33471991, 25741868
SCV003850016	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

SCV000184835

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Feb 28, 2018)

germline

clinical testing

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

Citation Link,

SCV000911449

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 7, 2022)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV003850016

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

BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families.

Claes K, Poppe B, Coene I, Paepe AD, Messiaen L.

Br J Cancer. 2004 Mar 22;90(6):1244-51.

PubMed [citation]

PMID:: 15026808
PMCID:: PMC2409651

Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls.

Momozawa Y, Iwasaki Y, Parsons MT, Kamatani Y, Takahashi A, Tamura C, Katagiri T, Yoshida T, Nakamura S, Sugano K, Miki Y, Hirata M, Matsuda K, Spurdle AB, Kubo M.

Nat Commun. 2018 Oct 4;9(1):4083. doi: 10.1038/s41467-018-06581-8.

PubMed [citation]

PMID:: 30287823
PMCID:: PMC6172276

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV000184835.8

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

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, SCV000911449.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This missense variant replaces arginine with histidine at codon 448 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 one suspected hereditary breast and ovarian cancer family (PMID: 15026808) and in a prostate cancer case-control study in 2/7636 cases and 3/12366 unaffected individuals (PMID: 31214711). This variant also has been reported in breast and pancreatic cancer case-control studies in which this variant was detected only in unaffected individuals and was absent in cancer cases (PMID: 30287823, 32980694, 33471991). This variant has been identified in 1/248242 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, SCV003850016.1

#	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: Jun 2, 2024

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