NM_000059.4(BRCA2):c.4271C>G (p.Ser1424Cys) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Mar 1, 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:: RCV000590783.21

Allele description [Variation Report for NM_000059.4(BRCA2):c.4271C>G (p.Ser1424Cys)]

NM_000059.4(BRCA2):c.4271C>G (p.Ser1424Cys)

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.4271C>G (p.Ser1424Cys)

HGVS:

NC_000013.11:g.32338626C>G
NG_012772.3:g.28147C>G
NM_000059.4:c.4271C>GMANE SELECT
NP_000050.2:p.Ser1424Cys
NP_000050.3:p.Ser1424Cys
LRG_293t1:c.4271C>G
LRG_293:g.28147C>G
LRG_293p1:p.Ser1424Cys
NC_000013.10:g.32912763C>G
NM_000059.3:c.4271C>G
U43746.1:n.4499C>G
p.S1424C

Protein change:

S1424C

Links:

dbSNP: rs80358664

NCBI 1000 Genomes Browser:

rs80358664

Molecular consequence:

NM_000059.4:c.4271C>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
SCV000329136	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely benign (Jun 10, 2021)	germline	clinical testing	Citation Link,
SCV000885083	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Likely benign (Jul 23, 2017)	germline	clinical testing	Citation Link,
SCV004219623	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Jun 10, 2023)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 31131967, 19491284, 24607278, 25682074, 26467025
SCV004226422	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 13, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 18824701, 19491284, 21120943, 24607278, 25682074, 31131967, 25741868
SCV004811120	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely benign (Mar 1, 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	unknown	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	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

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

Clinically applicable models to characterize BRCA1 and BRCA2 variants of uncertain significance.

Spearman AD, Sweet K, Zhou XP, McLennan J, Couch FJ, Toland AE.

J Clin Oncol. 2008 Nov 20;26(33):5393-400. doi: 10.1200/JCO.2008.17.8228. Epub 2008 Sep 29. Erratum in: J Clin Oncol. 2009 May 10;27(14):2415.

PubMed [citation]

PMID:: 18824701
PMCID:: PMC2651073

See all PubMed Citations (8)

Details of each submission

From GeneDx, SCV000329136.6

#	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 associated with the following publications: (PMID: 19491284, 21120943, 24607278, 26689913, 18824701, 25682074, 28324225, 31131967, 27535533)

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000885083.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004219623.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This variant has been characterized as being benign in a multifactorial likelihood study (PMID: 31131967 (2019)). In the published literature, the variant has been reported in individuals/families with breast and/or ovarian cancer (PMID: 19491284 (2009), 24607278 (2014), 25682074 (2015)), as well as breast cancer cases and unaffected control individuals in a large-scale breast cancer association study (PMID: 33471991, see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). The frequency of this variant in the general population, 0.000024 (3/127176 chromosomes, http://gnomad.broadinstitute.org), is uninformative in 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 Mayo Clinic Laboratories, Mayo Clinic, SCV004226422.1

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

Description

BP6, PM2

#	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 CeGaT Center for Human Genetics Tuebingen, SCV004811120.1

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

Description

BRCA2: BP1, BP4

#	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

Last Updated: Apr 20, 2024

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