NM_000059.4(BRCA2):c.1427C>G (p.Ser476Cys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: May 8, 2023
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:: RCV000132255.16

Allele description [Variation Report for NM_000059.4(BRCA2):c.1427C>G (p.Ser476Cys)]

NM_000059.4(BRCA2):c.1427C>G (p.Ser476Cys)

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.1427C>G (p.Ser476Cys)

Other names:

p.S476C:TCT>TGT

HGVS:

NC_000013.11:g.32332905C>G
NG_012772.3:g.22426C>G
NM_000059.4:c.1427C>GMANE SELECT
NP_000050.2:p.Ser476Cys
NP_000050.3:p.Ser476Cys
LRG_293t1:c.1427C>G
LRG_293:g.22426C>G
LRG_293p1:p.Ser476Cys
NC_000013.10:g.32907042C>G
NM_000059.3:c.1427C>G
U43746.1:n.1655C>G
p.S476C

Nucleotide change:

1655C>G

Protein change:

S476C

Links:

dbSNP: rs80358431

NCBI 1000 Genomes Browser:

rs80358431

Molecular consequence:

NM_000059.4:c.1427C>G - 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
SCV000187338	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (May 8, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000903873	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Apr 21, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002533232	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Aug 25, 2021)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 33471991, 26689913 Citation Link,
SCV003851379	University of Washington Department of Laboratory Medicine, University of Washington	criteria provided, single submitter (Dines et al. (Genet Med. 2020))	Likely benign (Mar 23, 2023)	germline	curation	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, curation

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

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 (4)

Details of each submission

From Ambry Genetics, SCV000187338.9

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

Description

The p.S476C variant (also known as c.1427C>G), located in coding exon 9 of the BRCA2 gene, results from a C to G substitution at nucleotide position 1427. The serine at codon 476 is replaced by cysteine, an amino acid with dissimilar properties. 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 Color Diagnostics, LLC DBA Color Health, SCV000903873.1

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

From Sema4, Sema4, SCV002533232.1

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

#	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 University of Washington Department of Laboratory Medicine, University of Washington, SCV003851379.1

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

Description

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).

#	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: May 7, 2024

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