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

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

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 15, 2019
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:: RCV000589633.3

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_007294.4: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
NM_007294.3:c.5123C>T
NR_027676.2:n.5300C>T
p.A1708V

Nucleotide change:

5242C>T

Protein change:

A1661V

Links:

dbSNP: rs28897696

Molecular consequence:

NM_007294.4: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)

Identifiers:: MedGen: CN517202

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000210201	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Dec 6, 2017)	germline	clinical testing	Citation Link,
SCV001133610	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics Criteria)	Uncertain significance (Aug 15, 2019)	germline	clinical testing	PubMed (15) [See all records that cite these PMIDs] 26689913, 27495310, 26287763, 22889855, 21702907, 17403394, 15744030, 12161611, 16489001, 18036263, 20516115, 25637381, 24055113, 22034289, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000210201

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Dec 6, 2017)

germline

clinical testing

Citation Link,

SCV001133610

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics Criteria)

Uncertain significance
(Aug 15, 2019)

germline

clinical testing

PubMed (15)
[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

Patterns and functional implications of rare germline variants across 12 cancer types.

Lu C, Xie M, Wendl MC, Wang J, McLellan MD, Leiserson MD, Huang KL, Wyczalkowski MA, Jayasinghe R, Banerjee T, Ning J, Tripathi P, Zhang Q, Niu B, Ye K, Schmidt HK, Fulton RS, McMichael JF, Batra P, Kandoth C, Bharadwaj M, Koboldt DC, et al.

Nat Commun. 2015 Dec 22;6:10086. doi: 10.1038/ncomms10086.

PubMed [citation]

PMID:: 26689913
PMCID:: PMC4703835

Characterization of BRCA1 and BRCA2 variants found in a Norwegian breast or ovarian cancer cohort.

Jarhelle E, Riise Stensland HM, Mæhle L, Van Ghelue M.

Fam Cancer. 2017 Jan;16(1):1-16. doi: 10.1007/s10689-016-9916-2.

PubMed [citation]

PMID:: 27495310

See all PubMed Citations (15)

Details of each submission

From GeneDx, SCV000210201.14

#	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 denoted BRCA1 c.5123C>T at the cDNA level, p.Ala1708Val (A1708V) at the protein level, and results in the change of an Alanine to a Valine (GCG>GTG). Using alternate nomenclature, this variant has been previously published as BRCA1 5242C>T. BRCA1 Ala1708Val has been observed in several individuals with a personal and/or family history of breast cancer and in an individual with renal cancer (Chenevix-Trench 2006, Fackenthal 2012, Lu 2015, Pal 2015), but was also present in large cohorts of control individuals undergoing whole exome sequencing (Dorschner 2013, Amendola 2015). In vitro functional studies have reported mixed results for BRCA1 Ala1708Val. Although some studies demonstrate a severe folding defect, compromised binding activity and specificity, diminished homologous recombination repair activity, and decreased transcriptional activation as compared to wild type, others have reported intermediate transcriptional activation and normal foci formation in response to DNA damage (Lovelock 2007, Lee 2010, Lu 2015). Lovelock et al. (2007) suggest that BRCA1 Ala1708Val may represent a pathogenic variant with reduced penetrance. BRCA1 Ala1708Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA1 Ala1708Val is located in the BRCT 1 domain and a region known to interact with multiple other proteins (UniProt, Paul 2014) . In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Ala1708Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001133610.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (15)

#	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: Dec 25, 2021

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