NM_007294.4(BRCA1):c.5123C>T (p.Ala1708Val) AND Hereditary breast and ovarian cancer syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 7, 2020
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:: RCV000048803.13

Allele description

NM_007294.4(BRCA1):c.5123C>T (p.Ala1708Val)

Gene:

BRCA1:BRCA1 DNA repair associated [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q21.31

Genomic location:

Preferred name:

NM_007294.4(BRCA1):c.5123C>T (p.Ala1708Val)

Other names:

p.A1708V:GCG>GTG

HGVS:

NC_000017.11:g.43063903G>A
NG_005905.2:g.154081C>T
NM_007294.3:c.5123C>T
NM_007294.4:c.5123C>TMANE SELECT
NM_007297.4:c.4982C>T
NM_007298.3:c.1811C>T
NM_007299.4:c.1811C>T
NM_007300.4:c.5186C>T
NP_009225.1:p.Ala1708Val
NP_009225.1:p.Ala1708Val
NP_009228.2:p.Ala1661Val
NP_009229.2:p.Ala604Val
NP_009230.2:p.Ala604Val
NP_009231.2:p.Ala1729Val
LRG_292t1:c.5123C>T
LRG_292:g.154081C>T
LRG_292p1:p.Ala1708Val
NC_000017.10:g.41215920G>A
NM_007294.2:c.5123C>T
NR_027676.2:n.5300C>T
p.A1708V

Nucleotide change:

5242C>T

Protein change:

A1661V

Links:

dbSNP: rs28897696

Molecular consequence:

NM_007294.3:c.5123C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_007294.4:c.5123C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_007297.4:c.4982C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_007298.3:c.1811C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_007299.4:c.1811C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_007300.4:c.5186C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_027676.2:n.5300C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Functional consequence:

functionally_normal [Sequence Ontology: SO:0002219] - Comment(s)

Condition(s)

Name:: Hereditary breast and ovarian cancer syndrome (HBOC)
Synonyms:: Hereditary breast and ovarian cancer; Hereditary breast and ovarian cancer syndrome (HBOC)
Identifiers:: MONDO: 0003582; MONDO: MONDO:0003582; MeSH: D061325; MedGen: C0677776; Orphanet: 145; OMIM: PS604370

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000076816	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 7, 2020)	germline	clinical testing	PubMed (14) [See all records that cite these PMIDs] 18036263, 23867111, 26287763, 19404736, 20516115, 27495310, 22034289, 16489001, 30209399, 15923272, 26689913, 11802208, 1157798, 28492532
SCV000591584	Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR)	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 27, 2015)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16489001, 24055113, 20516115, 18036263, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000076816

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 7, 2020)

germline

clinical testing

PubMed (14)
[See all records that cite these PMIDs]

SCV000591584

Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR)

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 27, 2015)

germline

clinical testing

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

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A high-throughput functional complementation assay for classification of BRCA1 missense variants.

Bouwman P, van der Gulden H, van der Heijden I, Drost R, Klijn CN, Prasetyanti P, Pieterse M, Wientjens E, Seibler J, Hogervorst FB, Jonkers J.

Cancer Discov. 2013 Oct;3(10):1142-55. doi: 10.1158/2159-8290.CD-13-0094. Epub 2013 Jul 18.

PubMed [citation]

PMID:: 23867111

A high frequency of BRCA mutations in young black women with breast cancer residing in Florida.

Pal T, Bonner D, Cragun D, Monteiro AN, Phelan C, Servais L, Kim J, Narod SA, Akbari MR, Vadaparampil ST.

Cancer. 2015 Dec 1;121(23):4173-80. doi: 10.1002/cncr.29645. Epub 2015 Aug 19.

PubMed [citation]

PMID:: 26287763
PMCID:: PMC4666784

See all PubMed Citations (16)

Details of each submission

From Invitae, SCV000076816.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

This sequence change replaces alanine with valine at codon 1708 of the BRCA1 protein (p.Ala1708Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs28897696, ExAC 0.04%). This variant has been reported in individuals with a personal and/or family history of breast cancer (PMID: 16489001, 18036263, 22034289, 26287763, 27495310), and an individual affected with kidney cancer (PMID: 26689913). In addition, it has been found in an individual with ovarian cancer (Invitae). However, in that individual a pathogenic allele was also identified in BRCA2, which suggests that this c.5123C>T variant was not the primary cause of disease. This variant is also known as 5242C>T (A1708V) in the literature. ClinVar contains an entry for this variant (Variation ID: 37640). Experimental studies have shown conflicting results for the effect of this missense change on BRCA1 structure and function. This variant caused decreased stability and compromised transcriptional activation, phosphopeptide binding (PMID: 20516115), and homology-directed repair activity (PMID: 26689913). However, in a different study, a protein with this missense variant showed normal stability and a relatively smaller decrease in transcriptional activity (PMID: 18036263). Additionally, a study utilizing a saturation genome editing (SGE) method has reported that this variant does not substantially affect BRCA1 protein function (PMID: 30209399). A different missense substitution at this codon (p.Ala1708Glu) has been determined to be pathogenic (PMID: 1157798, 11802208, 15923272, 19404736, 23867111). This suggests that the alanine residue is critical for BRCA1 protein function and that other missense substitutions at this position may also be pathogenic. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been 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 Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000591584.1

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

#	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: Apr 2, 2021

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