NM_000059.4(BRCA2):c.455C>A (p.Thr152Lys) AND Breast-ovarian cancer, familial, susceptibility to, 2

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Dec 13, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000113613.18

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]

Observations:

Condition(s)

Name:: Breast-ovarian cancer, familial, susceptibility to, 2 (BROVCA2)
Synonyms:: Breast-ovarian cancer, familial 2
Identifiers:: MONDO: MONDO:0012933; MedGen: C2675520; Orphanet: 145; OMIM: 612555

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000146890	Breast Cancer Information Core (BIC) (BRCA2)	no assertion criteria provided	Uncertain significance (May 29, 2002)	germline	clinical testing
SCV000189306	Sharing Clinical Reports Project (SCRP)	no assertion criteria provided	Likely benign (Feb 28, 2011)	germline	clinical testing
SCV001548651	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Uncertain significance	unknown	clinical testing
SCV004846779	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 13, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 20104584, 20215541, 27060066, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	1	not provided	not provided	1	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	2	not provided	not provided	108544	not provided	clinical testing
Western European	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.

Borg A, Haile RW, Malone KE, Capanu M, Diep A, Törngren T, Teraoka S, Begg CB, Thomas DC, Concannon P, Mellemkjaer L, Bernstein L, Tellhed L, Xue S, Olson ER, Liang X, Dolle J, Børresen-Dale AL, Bernstein JL.

Hum Mutat. 2010 Mar;31(3):E1200-40. doi: 10.1002/humu.21202.

PubMed [citation]

PMID:: 20104584
PMCID:: PMC2928257

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 Breast Cancer Information Core (BIC) (BRCA2), SCV000146890.1

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

#	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		1	not provided	not provided	not provided

From Sharing Clinical Reports Project (SCRP), SCV000189306.1

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

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

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001548651.1

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

Description

The BRCA2 p.Thr152Lys variant was identified in 2 of 5582 proband chromosomes (frequency: 0.0004) from individuals or families with hereditary breast and ovarian cancer (Borg 2010, Sanz 2010). The variant was identified in dbSNP (rs80358691) as â€šÃ„Ãºwith other alleleâ€šÃ„Ã¹ and ClinVar (classified as uncertain significance by Invitae, Color, GeneDx, Ambry Genetics and 2 other submitters; and as likely benign by SCRP). The variant was not identified in LOVD 3.0 or UMD-LSDB. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). An RT-PCR experiment detected a partial deletion of exon 5 indicating the variant may cause splicing defects (Sanz 2010); however, further analysis of alternative BRCA2 transcripts identified the partial deletion of exon 5 in cells lacking the variant, indicating this event may be independent of the mutation (Fackenthal 2016). Although the p.Thr152 residue is not conserved in mammals and other organisms, 4 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. 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	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004846779.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant replaces threonine with lysine at codon 152 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). An RNA study has shown this variant results in transcripts with partial exon 5 skipping (PMID: 20215541), however a later study showed these transcripts also occur in cells lacking this variant (PMID: 27060066). This variant has been reported in an individual affected with breast cancer (PMID: 20104584). This variant has not been identified 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	108544	not provided	not provided		2	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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