NM_000059.4(BRCA2):c.440A>T (p.Gln147Leu) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 22, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000589401.10

Allele description [Variation Report for NM_000059.4(BRCA2):c.440A>T (p.Gln147Leu)]

NM_000059.4(BRCA2):c.440A>T (p.Gln147Leu)

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.440A>T (p.Gln147Leu)

HGVS:

NC_000013.11:g.32326115A>T
NG_012772.3:g.15636A>T
NM_000059.4:c.440A>TMANE SELECT
NP_000050.2:p.Gln147Leu
NP_000050.3:p.Gln147Leu
LRG_293t1:c.440A>T
LRG_293:g.15636A>T
LRG_293p1:p.Gln147Leu
NC_000013.10:g.32900252A>T
NM_000059.3:c.440A>T
p.Q147L

Nucleotide change:

668A>T

Protein change:

Q147L

Links:

dbSNP: rs80358674

NCBI 1000 Genomes Browser:

rs80358674

Molecular consequence:

NM_000059.4:c.440A>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000568903	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Aug 7, 2017)	germline	clinical testing	Citation Link,
SCV000600588	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Sep 22, 2022)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 33471991, 30883759, 25186627, 31131967, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000568903

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Aug 7, 2017)

germline

clinical testing

Citation Link,

SCV000600588

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(Sep 22, 2022)

unknown

clinical testing

PubMed (5)
[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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.

Breast Cancer Association Consortium., Dorling L, Carvalho S, Allen J, González-Neira A, Luccarini C, Wahlström C, Pooley KA, Parsons MT, Fortuno C, Wang Q, Bolla MK, Dennis J, Keeman R, Alonso MR, Álvarez N, Herraez B, Fernandez V, Núñez-Torres R, Osorio A, Valcich J, Li M, et al.

N Engl J Med. 2021 Feb 4;384(5):428-439. doi: 10.1056/NEJMoa1913948. Epub 2021 Jan 20.

PubMed [citation]

PMID:: 33471991
PMCID:: PMC7611105

Mis-splicing in breast cancer: identification of pathogenic BRCA2 variants by systematic minigene assays.

Fraile-Bethencourt E, Valenzuela-Palomo A, Díez-Gómez B, Goina E, Acedo A, Buratti E, Velasco EA.

J Pathol. 2019 Aug;248(4):409-420. doi: 10.1002/path.5268. Epub 2019 Apr 23.

PubMed [citation]

PMID:: 30883759

See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV000568903.5

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

Description

This variant is denoted BRCA2 c.440A>T at the cDNA level, p.Gln147Leu (Q147L) at the protein level, and results in the change of a Glutamine to a Leucine (CAA>CTA). Using alternate nomenclature, this variant would be defined as BRCA2 668A>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Gln147Leu was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Gln147Leu occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Gln147Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000600588.3

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

Description

The frequency of this variant in the general population, 0.000008 (2/250964 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 33471991 (2021), 25186627 (2015, see also see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). A multifactorial analysis study has reported that this variant is likely not pathogenic (PMID: 31131967 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

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

Last Updated: Nov 10, 2024

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