NM_007294.4(BRCA1):c.4484G>A (p.Arg1495Lys) AND not provided

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

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jun 21, 2018
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:: RCV000479568.1

Allele description

NM_007294.4(BRCA1):c.4484G>A (p.Arg1495Lys)

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.4484G>A (p.Arg1495Lys)

HGVS:

NC_000017.11:g.43076488C>T
NG_005905.2:g.141496G>A
NM_007294.3:c.4484G>A
NM_007294.4:c.4484G>AMANE SELECT
NM_007297.4:c.4343G>A
NM_007298.3:c.1172G>A
NM_007299.4:c.1172G>A
NM_007300.4:c.4547G>A
NP_009225.1:p.Arg1495Lys
NP_009225.1:p.Arg1495Lys
NP_009228.2:p.Arg1448Lys
NP_009229.2:p.Arg391Lys
NP_009230.2:p.Arg391Lys
NP_009231.2:p.Arg1516Lys
LRG_292t1:c.4484G>A
LRG_292:g.141496G>A
LRG_292p1:p.Arg1495Lys
NC_000017.10:g.41228505C>T
NM_007294.4:c.4484G>A
NR_027676.2:n.4661G>A
U14680.1:n.4603G>A
p.R1495K

Nucleotide change:

4603G>A

Protein change:

R1448K

Links:

dbSNP: rs80357389

NCBI 1000 Genomes Browser:

rs80357389

Molecular consequence:

NM_007294.3:c.4484G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_007294.4:c.4484G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_007297.4:c.4343G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_007298.3:c.1172G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_007299.4:c.1172G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_007300.4:c.4547G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_027676.2:n.4661G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Identifiers:: MedGen: CN517202

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000568404	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Jun 29, 2017)	germline	clinical testing	Citation Link,
SCV000887697	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics Criteria)	Likely pathogenic (Jun 21, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000568404

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Jun 29, 2017)

germline

clinical testing

Citation Link,

SCV000887697

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics Criteria)

Likely pathogenic
(Jun 21, 2018)

germline

clinical testing

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	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 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

Details of each submission

From GeneDx, SCV000568404.5

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

Description

This pathogenic variant is denoted BRCA1 c.4484G>A at the cDNA level. Using alternate nomenclature, this pathogenic variant would be defined as BRCA1 4603G>A. Located in the last nucleotide of exon 14, it disrupts a natural splice donor site and causes abnormal splicing. RNA analysis has demonstrated that BRCA1 c.4484G>A causes skipping of exon 14 (Houdayer 2012). Although the nucleotide substitution results in the change of an Arginine to a Lysine at codon 1495, and is called BRCA1 Arg1495Lys in the literature, we are using only the nucleotide nomenclature to refer to the variant since the defect is determined to be one of splicing rather than a resulting missense variant. BRCA1 c.4484G>A was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). The nucleotide which is altered, a guanine (G) at base 4484, is conserved across species. This variant has been observed in individuals with breast and/or ovarian cancer, as well as in individuals who underwent evaluation for hereditary breast and ovarian cancer (Judkins 2005, Alsop 2012, Lecarpentier 2012, George 2013, Fernandes 2016). Based on currently available evidence, we consider this variant to be pathogenic.

#	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, SCV000887697.1

#	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

Last Updated: Sep 23, 2021

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