NM_000059.4(BRCA2):c.5270A>G (p.Tyr1757Cys) AND not provided

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jul 2, 2024
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:: RCV000173972.17

Allele description [Variation Report for NM_000059.4(BRCA2):c.5270A>G (p.Tyr1757Cys)]

NM_000059.4(BRCA2):c.5270A>G (p.Tyr1757Cys)

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.5270A>G (p.Tyr1757Cys)

HGVS:

NC_000013.11:g.32339625A>G
NG_012772.3:g.29146A>G
NM_000059.4:c.5270A>GMANE SELECT
NP_000050.2:p.Tyr1757Cys
NP_000050.3:p.Tyr1757Cys
LRG_293t1:c.5270A>G
LRG_293:g.29146A>G
LRG_293p1:p.Tyr1757Cys
NC_000013.10:g.32913762A>G
NM_000059.3:c.5270A>G
p.Y1757C

Nucleotide change:

5498A>G

Protein change:

Y1757C

Links:

dbSNP: rs587776466

NCBI 1000 Genomes Browser:

rs587776466

Molecular consequence:

NM_000059.4:c.5270A>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
SCV000225179	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Uncertain significance (May 11, 2015)	germline	clinical testing	Citation Link,
SCV001470219	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Jul 2, 2024)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 25980754, 31911673, 35957908, 35264596, 28392550, 33471991, 26467025
SCV001787996	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Apr 8, 2024)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000225179

Eurofins Ntd Llc (ga)

criteria provided, single submitter

(EGL Classification Definitions 2015)

Uncertain significance
(May 11, 2015)

germline

clinical testing

Citation Link,

SCV001470219

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(Jul 2, 2024)

unknown

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV001787996

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Apr 8, 2024)

germline

clinical testing

Citation Link

Help

Summary from all submissions

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

Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome.

Yurgelun MB, Allen B, Kaldate RR, Bowles KR, Judkins T, Kaushik P, Roa BB, Wenstrup RJ, Hartman AR, Syngal S.

Gastroenterology. 2015 Sep;149(3):604-13.e20. doi: 10.1053/j.gastro.2015.05.006. Epub 2015 May 14.

PubMed [citation]

PMID:: 25980754
PMCID:: PMC4550537

Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots".

Dines JN, Shirts BH, Slavin TP, Walsh T, King MC, Fowler DM, Pritchard CC.

Genet Med. 2020 May;22(5):825-830. doi: 10.1038/s41436-019-0740-6. Epub 2020 Jan 8.

PubMed [citation]

PMID:: 31911673
PMCID:: PMC7200594

See all PubMed Citations (7)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000225179.6

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001470219.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

The BRCA2 c.5270A>G (p.Tyr1757Cys) variant has been reported in the published literature in individuals with breast cancer (PMIDs: 35264596 (2022), 28392550 (2018)), suspected Lynch syndrome (PMID: 25980754 (2015)), as well as in reportedly healthy individuals (PMIDs: 35957908 (2022), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). This variant has been described to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.000012 (3/250310 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 GeneDx, SCV001787996.5

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 5498A>G; This variant is associated with the following publications: (PMID: 28392550, 25980754, 35264596, 33471991, 35957908)

#	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

Last Updated: May 25, 2025

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