NM_000059.4(BRCA2):c.695A>G (p.Tyr232Cys) AND not provided

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Apr 19, 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:: RCV000656999.19

Allele description [Variation Report for NM_000059.4(BRCA2):c.695A>G (p.Tyr232Cys)]

NM_000059.4(BRCA2):c.695A>G (p.Tyr232Cys)

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.695A>G (p.Tyr232Cys)

HGVS:

NC_000013.11:g.32330932A>G
NG_012772.3:g.20453A>G
NM_000059.4:c.695A>GMANE SELECT
NP_000050.2:p.Tyr232Cys
NP_000050.3:p.Tyr232Cys
LRG_293t1:c.695A>G
LRG_293:g.20453A>G
LRG_293p1:p.Tyr232Cys
NC_000013.10:g.32905069A>G
NM_000059.3:c.695A>G
p.Y232C

Protein change:

Y232C

Links:

dbSNP: rs372188754

NCBI 1000 Genomes Browser:

rs372188754

Molecular consequence:

NM_000059.4:c.695A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000232905	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Uncertain significance (Apr 16, 2015)	germline	clinical testing	Citation Link,
SCV000565866	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Sep 15, 2021)	germline	clinical testing	Citation Link,
SCV000889117	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Feb 13, 2023)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 30287823, 33471991, 31248605, 31396961, 32467295, 26467025
SCV004565077	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Uncertain significance (Apr 19, 2023)	germline	clinical testing	Citation Link

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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	not provided	not provided	clinical testing
not provided	germline	yes	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

Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls.

Momozawa Y, Iwasaki Y, Parsons MT, Kamatani Y, Takahashi A, Tamura C, Katagiri T, Yoshida T, Nakamura S, Sugano K, Miki Y, Hirata M, Matsuda K, Spurdle AB, Kubo M.

Nat Commun. 2018 Oct 4;9(1):4083. doi: 10.1038/s41467-018-06581-8.

PubMed [citation]

PMID:: 30287823
PMCID:: PMC6172276

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

See all PubMed Citations (6)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000232905.5

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

From GeneDx, SCV000565866.7

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

Description

Observed in individuals with a personal history of breast cancer, but also observed in controls (Momozawa 2018); Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 923A>G; This variant is associated with the following publications: (PMID: 30287823, 27071721)

#	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, SCV000889117.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The frequency of this variant in the general population, 0.00002 (5/250024 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 (PMIDs: 33471991 (2021) see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2), 30287823 (2018)), prostate cancer (PMID: 31248605 (2019)), and esophageal squamous cell carcinoma (PMID: 31396961 (2020)). Additionally, the variant has been reported in healthy individuals (PMIDs: 33471991 (2021) see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2), 32467295 (2020), 30287823 (2018)). 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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV004565077.1

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

Description

The BRCA2 c.695A>G; p.Tyr232Cys variant (rs372188754) is reported in the literature in individuals affected with breast cancer, prostate cancer, or esophageal squamous cell carcinoma without clear disease association (Ko 2020, Momozawa 2018, Wei 2019), and is also found in healthy controls (Momozawa 2018). This variant is reported in ClinVar (Variation ID: 141345), and is found in the general population with an overall allele frequency of 0.0020% (5/250024 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.279). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Ko JM et al. BRCA2 loss-of-function germline mutations are associated with esophageal squamous cell carcinoma risk in Chinese. Int J Cancer. 2020 Feb 15;146(4):1042-1051. PMID: 31396961. Momozawa Y et al. Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. Nat Commun. 2018 Oct 4;9(1):4083. PMID: 30287823. Wei Y et al. Germline DNA Repair Gene Mutation Landscape in Chinese Prostate Cancer Patients. Eur Urol. 2019 Sep;76(3):280-283. PMID: 31248605.

#	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: Nov 3, 2024

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