NM_000059.4(BRCA2):c.4318A>G (p.Lys1440Glu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: May 31, 2024
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:: RCV000130424.16

Allele description [Variation Report for NM_000059.4(BRCA2):c.4318A>G (p.Lys1440Glu)]

NM_000059.4(BRCA2):c.4318A>G (p.Lys1440Glu)

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.4318A>G (p.Lys1440Glu)

HGVS:

NC_000013.11:g.32338673A>G
NG_012772.3:g.28194A>G
NM_000059.4:c.4318A>GMANE SELECT
NP_000050.2:p.Lys1440Glu
NP_000050.3:p.Lys1440Glu
LRG_293t1:c.4318A>G
LRG_293:g.28194A>G
LRG_293p1:p.Lys1440Glu
NC_000013.10:g.32912810A>G
NM_000059.3:c.4318A>G
U43746.1:n.4546A>G
p.K1440E

Protein change:

K1440E

Links:

dbSNP: rs80358668

NCBI 1000 Genomes Browser:

rs80358668

Molecular consequence:

NM_000059.4:c.4318A>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

Recent activity

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hypothetical protein BvMPK_4331 [Phocaeicola vulgatus]
hypothetical protein BvMPK_4331 [Phocaeicola vulgatus]
gi|941513338|gnl|tueFrick|BvMPK_433 ALK86873.1|

Protein
phosphogluconate dehydratase [Klebsiella pneumoniae]
phosphogluconate dehydratase [Klebsiella pneumoniae]
gi|1429032437|emb|SSH04182.1||gnl|W CR|SSH04182

Protein
putative transcriptional regulator [Phocaeicola vulgatus]
putative transcriptional regulator [Phocaeicola vulgatus]
gi|941513340|gnl|tueFrick|BvMPK_433 ALK86875.1|

Protein
maturase K, partial (chloroplast) [Parinariopsis licaniiflora]
maturase K, partial (chloroplast) [Parinariopsis licaniiflora]
gi|440385421|gb|AGC03091.1|

Protein
Casein kinase I, putative [Cryptococcus gattii WM276]
Casein kinase I, putative [Cryptococcus gattii WM276]
gi|317460311|gnl|ubcmsl|CGB_D7320C| V22054.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000185288	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (May 31, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000906909	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 16, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23071527, 25741868
SCV003850414	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

SCV000185288

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(May 31, 2024)

germline

clinical testing

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

Citation Link,

SCV000906909

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 16, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV003850414

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

Effects of the missense mutations in canine BRCA2 on BRC repeat 3 functions and comparative analyses between canine and human BRC repeat 3.

Yoshikawa Y, Ochiai K, Morimatsu M, Suzuki Y, Wada S, Taoda T, Iwai S, Chikazawa S, Orino K, Watanabe K.

PLoS One. 2012;7(10):e45833. doi: 10.1371/journal.pone.0045833. Epub 2012 Oct 12.

PubMed [citation]

PMID:: 23071527
PMCID:: PMC3470543

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

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000185288.9

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

Description

The p.K1440E variant (also known as c.4318A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 4318. The lysine at codon 1440 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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, SCV000906909.3

#	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 lysine with glutamic acid at codon 1440 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). Functional studies have shown this variant decreases affinity of BRCA2 for RAD51 in mammalian two-hybrid assays (PMID: 23071527). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/242658 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, SCV003850414.1

#	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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