NM_000059.4(BRCA2):c.464G>C (p.Arg155Thr) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Apr 8, 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:: RCV000582907.13

Allele description [Variation Report for NM_000059.4(BRCA2):c.464G>C (p.Arg155Thr)]

NM_000059.4(BRCA2):c.464G>C (p.Arg155Thr)

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.464G>C (p.Arg155Thr)

Other names:

R115T; p.R155T:AGA>ACA

HGVS:

NC_000013.11:g.32326139G>C
NG_012772.3:g.15660G>C
NM_000059.4:c.464G>CMANE SELECT
NP_000050.2:p.Arg155Thr
NP_000050.3:p.Arg155Thr
LRG_293t1:c.464G>C
LRG_293:g.15660G>C
LRG_293p1:p.Arg155Thr
NC_000013.10:g.32900276G>C
NM_000059.3:c.464G>C

Nucleotide change:

692G>C

Protein change:

R155T

Links:

dbSNP: rs377639990

NCBI 1000 Genomes Browser:

rs377639990

Molecular consequence:

NM_000059.4:c.464G>C - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000688885	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 2, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 32438681, 33471991, 34178674, 34572941, 25741868
SCV001184627	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (May 26, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27062684, 32438681, 34178674 Citation Link,
SCV004814100	Mendelics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Apr 8, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000688885

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 2, 2022)

germline

clinical testing

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

SCV001184627

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(May 26, 2023)

germline

clinical testing

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

Citation Link,

SCV004814100

Mendelics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Apr 8, 2024)

unknown

clinical testing

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
not provided	unknown	unknown	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

Spectrum of Germline Pathogenic Variants in BRCA1/2 Genes in the Apulian Southern Italy Population: Geographic Distribution and Evidence for Targeted Genetic Testing.

Patruno M, De Summa S, Resta N, Caputo M, Costanzo S, Digennaro M, Pilato B, Bagnulo R, Pantaleo A, Simone C, Natalicchio MI, De Matteis E, Tarantino P, Tommasi S, Paradiso A.

Cancers (Basel). 2021 Sep 21;13(18). doi:pii: 4714. 10.3390/cancers13184714.

PubMed [citation]

PMID:: 34572941
PMCID:: PMC8467705

See all PubMed Citations (6)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000688885.4

#	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 arginine with threonine at codon 155 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals with a personal and/or family history of breast or ovarian cancer (PMID: 32438681, 34178674, 34572941). An individual affected with breast cancer carried both this variant and a pathogenic BRCA1 co-variant (PMID: 32438681). This variant also has been reported in a breast cancer case-control meta-analysis in 1/53460 unaffected individuals and absent in 60466 cases (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_007554). This variant has been identified in 1/251052 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 Ambry Genetics, SCV001184627.5

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

Description

The p.R155T variant (also known as c.464G>C), located in coding exon 4 of the BRCA2 gene, results from a G to C substitution at nucleotide position 464. The arginine at codon 155 is replaced by threonine, an amino acid with similar properties. In a study of 1854 high-risk breast/ovarian cancer families in Italy, this alteration was detected in 1 family (Azzollini J et al, Eur J Intern Med. 2016 Jul;32:65-71). In another study, this alteration was identified in a patient with breast cancer; however this individual was also found to carry a pathogenic mutation in the BRCA1 gene (Santonocito C et al, Cancers (Basel). 2020 May;12:). This alteration was also identified within a cohort of 874 unrelated Italian breast or ovarian cancer patients undergoing genetic testing based on suspicion for HBOC (Fanale D et al. Front Oncol, 2021 Jun;11:682445). This amino acid position is well 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mendelics, SCV004814100.1

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

#	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: Sep 29, 2024

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