NM_000059.4(BRCA2):c.440A>T (p.Gln147Leu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Aug 2, 2023
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:: RCV000164577.16

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]

Observations:

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000215235	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Uncertain significance (Sep 23, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25186627, 30883759 Citation Link,
SCV001347750	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 2, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25186627, 30883759, 31131967, 33471991, 25741868
SCV002533870	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Mar 5, 2022)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 25186627, 33471991, 30883759 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000215235

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Uncertain significance
(Sep 23, 2021)

germline

clinical testing

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

Citation Link,

SCV001347750

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 2, 2023)

germline

clinical testing

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

SCV002533870

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Mar 5, 2022)

germline

curation

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	1	not provided	clinical testing, curation

Citations

PubMed

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification.

Parsons MT, Tudini E, Li H, Hahnen E, Wappenschmidt B, Feliubadaló L, Aalfs CM, Agata S, Aittomäki K, Alducci E, Alonso-Cerezo MC, Arnold N, Auber B, Austin R, Azzollini J, Balmaña J, Barbieri E, Bartram CR, Blanco A, Blümcke B, Bonache S, Bonanni B, et al.

Hum Mutat. 2019 Sep;40(9):1557-1578. doi: 10.1002/humu.23818.

PubMed [citation]

PMID:: 31131967
PMCID:: PMC6772163

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 (5)

Details of each submission

From Ambry Genetics, SCV000215235.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (2)

Description

The p.Q147L variant (also known as c.440A>T), located in coding exon 4 of the BRCA2 gene, results from an A to T substitution at nucleotide position 440. The glutamine at codon 147 is replaced by leucine, an amino acid with dissimilar properties. This alteration was detected on a 25-gene panel test in a woman who was diagnosed with breast cancer before age 50 (unspecified ancestry) (Tung N et al. Cancer, 2015 Jan;121:25-33). This amino acid position is poorly 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	1	not provided	not provided		1	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV001347750.3

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

Description

This missense variant replaces glutamine with leucine at codon 147 of the BRCA2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). An RNA study suggests that this variant does not significantly impact splicing (PMID: 30883759). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in at least two individuals affected with breast cancer (PMID: 25186627, 33471991; Leiden Open Variation Database DB-ID BRCA2_001583). A multifactorial analysis has reported segregation and family history likelihood ratios for pathogenicity based on one pedigree of 0.5353 and 0.7695, respectively (PMID: 31131967). This variant has been identified in 2/250964 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 Sema4, Sema4, SCV002533870.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (3)

#	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: Apr 20, 2024

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