NM_007294.4(BRCA1):c.5123C>T (p.Ala1708Val) AND not specified

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

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 15, 2019
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000212194.5

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)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000494396	Integrated Genetics/Laboratory Corporation of America	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Apr 15, 2019)	germline	clinical testing	PubMed (18) [See all records that cite these PMIDs] 20516115, 16489001, 21702907, 24055113, 22034289, 15744030, 18036263, 17403394, 22889855, 11802208, 12161611, 26287763, 25637381, 26689913, 27495310, 30458859, 30263132, 28781887 Citation Link,
SCV000587467	Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto - The Canadian Open Genetics Repository (COGR)	no assertion criteria provided	Uncertain significance (Jan 31, 2014)	germline	research

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000494396

Integrated Genetics/Laboratory Corporation of America

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Apr 15, 2019)

germline

clinical testing

PubMed (18)
[See all records that cite these PMIDs]

Citation Link,

SCV000587467

Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto - The Canadian Open Genetics Repository (COGR)

no assertion criteria provided

Uncertain significance
(Jan 31, 2014)

germline

research

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	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Comprehensive analysis of missense variations in the BRCT domain of BRCA1 by structural and functional assays.

Lee MS, Green R, Marsillac SM, Coquelle N, Williams RS, Yeung T, Foo D, Hau DD, Hui B, Monteiro AN, Glover JN.

Cancer Res. 2010 Jun 15;70(12):4880-90. doi: 10.1158/0008-5472.CAN-09-4563. Epub 2010 Jun 1.

PubMed [citation]

PMID:: 20516115
PMCID:: PMC3040717

Genetic and histopathologic evaluation of BRCA1 and BRCA2 DNA sequence variants of unknown clinical significance.

Chenevix-Trench G, Healey S, Lakhani S, Waring P, Cummings M, Brinkworth R, Deffenbaugh AM, Burbidge LA, Pruss D, Judkins T, Scholl T, Bekessy A, Marsh A, Lovelock P, Wong M, Tesoriero A, Renard H, Southey M, Hopper JL, Yannoukakos K, Brown M, Easton D, et al.

Cancer Res. 2006 Feb 15;66(4):2019-27.

PubMed [citation]

PMID:: 16489001

See all PubMed Citations (18)

Details of each submission

From Integrated Genetics/Laboratory Corporation of America, SCV000494396.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (18)

Description

Variant summary: BRCA1 c.5123C>T (p.Ala1708Val) results in a non-conservative amino acid change located in the BRCT domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251672 control chromosomes (gnomAD and one publication). The variant, c.5123C>T, has been reported in the literature in individuals affected with cancers (Chenevix-Trench_2006, Fackenthal_2012, Lovelock_2007, Caldes_2002, Pal_2015, Lu_2015, Jarhelle_2016). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. This variant was reported in FLOSSIES database and co-occurrences with another pathogenic variant have been reported in ClinVar (not specified), providing supporting evidence for a benign role. Functional studies showed that this variant leads to varied effects depending upon types of assays performed (Lovelock_2007, Lee_2008, Lu_2015). The variant had normal effect on protein expression and foci formation in response to DNA damage but had intermediate to strong effect on transcription, protein folding, centrosome amplification and phosphopeptide binding. The possibility of the variant to be a mild causative mutation associated with a late onset of the disease cannot be ruled out. Another missense change at the same residue A1708E is a known pathogenic variant; while A1708E leads to charge change, A1708V does not. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as 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 Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto - The Canadian Open Genetics Repository (COGR), SCV000587467.1

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

#	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 18, 2021

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