NM_000465.4(BARD1):c.1268A>G (p.Lys423Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Mar 27, 2024
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:: RCV000166718.13

Allele description [Variation Report for NM_000465.4(BARD1):c.1268A>G (p.Lys423Arg)]

NM_000465.4(BARD1):c.1268A>G (p.Lys423Arg)

Gene:

BARD1:BRCA1 associated RING domain 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q35

Genomic location:

Preferred name:

NM_000465.4(BARD1):c.1268A>G (p.Lys423Arg)

HGVS:

NC_000002.12:g.214780606T>C
NG_012047.3:g.34106A>G
NM_000465.4:c.1268A>GMANE SELECT
NM_001282543.2:c.1211A>G
NM_001282545.2:c.215+16455A>G
NM_001282548.2:c.159-28051A>G
NM_001282549.2:c.364+11691A>G
NP_000456.2:p.Lys423Arg
NP_001269472.1:p.Lys404Arg
LRG_297t1:c.1268A>G
LRG_297:g.34106A>G
LRG_297p1:p.Lys423Arg
NC_000002.11:g.215645330T>C
NG_012047.2:g.34099A>G
NM_000465.2:c.1268A>G
NM_000465.3:c.1268A>G
NR_104212.2:n.1233A>G
NR_104215.2:n.1176A>G
p.K423R

Protein change:

K404R

Links:

dbSNP: rs749383704

NCBI 1000 Genomes Browser:

rs749383704

Molecular consequence:

NM_001282545.2:c.215+16455A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001282548.2:c.159-28051A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001282549.2:c.364+11691A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000465.4:c.1268A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001282543.2:c.1211A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_104212.2:n.1233A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_104215.2:n.1176A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000217528	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Mar 27, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000912089	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 21, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002526998	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Mar 18, 2022)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000217528

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Mar 27, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV000912089

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 21, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002526998

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Mar 18, 2022)

germline

curation

PubMed (1)
[See all records that cite this PMID]

Citation Link

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

Germline variants in DNA repair genes associated with hereditary breast and ovarian cancer syndrome: analysis of a 21 gene panel in the Brazilian population.

da Costa E Silva Carvalho S, Cury NM, Brotto DB, de Araujo LF, Rosa RCA, Texeira LA, Plaça JR, Marques AA, Peronni KC, Ruy PC, Molfetta GA, Moriguti JC, Carraro DM, Palmero EI, Ashton-Prolla P, de Faria Ferraz VE, Silva WA Jr.

BMC Med Genomics. 2020 Feb 10;13(1):21. doi: 10.1186/s12920-019-0652-y.

PubMed [citation]

PMID:: 32039725
PMCID:: PMC7011249

Details of each submission

From Ambry Genetics, SCV000217528.8

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

Description

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

#	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, SCV000912089.3

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

Description

This missense variant replaces lysine with arginine at codon 423 of the BARD1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hereditary breast and ovarian cancer (PMID: 32039725). This variant has been identified in 1/250918 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is 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 Sema4, Sema4, SCV002526998.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	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 29, 2024

ClinVar

Relating variation to medicine