NM_000059.4(BRCA2):c.455C>A (p.Thr152Lys) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 7, 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:: RCV000588748.11

Allele description [Variation Report for NM_000059.4(BRCA2):c.455C>A (p.Thr152Lys)]

NM_000059.4(BRCA2):c.455C>A (p.Thr152Lys)

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.455C>A (p.Thr152Lys)

Other names:

p.T152K:ACA>AAA

HGVS:

NC_000013.11:g.32326130C>A
NG_012772.3:g.15651C>A
NM_000059.4:c.455C>AMANE SELECT
NP_000050.2:p.Thr152Lys
NP_000050.3:p.Thr152Lys
LRG_293t1:c.455C>A
LRG_293:g.15651C>A
LRG_293p1:p.Thr152Lys
NC_000013.10:g.32900267C>A
NM_000059.3:c.455C>A
U43746.1:n.683C>A

Nucleotide change:

683C>A

Protein change:

T152K

Links:

dbSNP: rs80358691

NCBI 1000 Genomes Browser:

rs80358691

Molecular consequence:

NM_000059.4:c.455C>A - 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
SCV000210241	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Oct 24, 2017)	germline	clinical testing	Citation Link,
SCV002046894	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Sep 7, 2022)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21520273, 20215541, 20104584, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000210241

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Oct 24, 2017)

germline

clinical testing

Citation Link,

SCV002046894

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(Sep 7, 2022)

unknown

clinical testing

PubMed (4)
[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

Assessment of rare BRCA1 and BRCA2 variants of unknown significance using hierarchical modeling.

Capanu M, Concannon P, Haile RW, Bernstein L, Malone KE, Lynch CF, Liang X, Teraoka SN, Diep AT, Thomas DC, Bernstein JL; WECARE Study Collaborative Group., Begg CB.

Genet Epidemiol. 2011 Jul;35(5):389-97. doi: 10.1002/gepi.20587. Epub 2011 Apr 25.

PubMed [citation]

PMID:: 21520273
PMCID:: PMC3111904

A high proportion of DNA variants of BRCA1 and BRCA2 is associated with aberrant splicing in breast/ovarian cancer patients.

Sanz DJ, Acedo A, Infante M, Durán M, Pérez-Cabornero L, Esteban-Cardeñosa E, Lastra E, Pagani F, Miner C, Velasco EA.

Clin Cancer Res. 2010 Mar 15;16(6):1957-67. doi: 10.1158/1078-0432.CCR-09-2564. Epub 2010 Mar 9.

PubMed [citation]

PMID:: 20215541

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000210241.12

#	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.455C>A at the cDNA level, p.Thr152Lys (T152K) at the protein level, and results in the change of a Threonine to a Lysine (ACA>AAA). This variant, also known as BRCA2 683C>A using alternate nomenclature, was observed in one individual with breast cancer (Borg 2010). Splicing functional minigene assays by Sanz et al. (2010) showed a splicing effect with partial skipping of exon 5, leading authors to classify this variant as uncertain. BRCA2 Thr152Lys was not observed in large population cohorts (Lek 2016). Since Threonine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Thr152Lys occurs at a position that is conserved across species 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 Thr152Lys 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, SCV002046894.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in at least one individual affected with breast cancer (PMID: 20104584 (2010)). Additionally, this variant was reported to cause aberrant BRCA2 mRNA splicing in one functional study (PMID: 21520273 (2011)), however, further studies are needed to confirm this observation. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. 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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