NM_000465.4(BARD1):c.353A>G (p.Asn118Ser) AND Familial cancer of breast

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Jan 21, 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:: RCV000468892.16

Allele description [Variation Report for NM_000465.4(BARD1):c.353A>G (p.Asn118Ser)]

NM_000465.4(BARD1):c.353A>G (p.Asn118Ser)

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.353A>G (p.Asn118Ser)

Other names:

p.N118S:AAT>AGT

HGVS:

NC_000002.12:g.214792308T>C
NG_012047.3:g.22404A>G
NM_000465.4:c.353A>GMANE SELECT
NM_001282543.2:c.296A>G
NM_001282545.2:c.215+4753A>G
NM_001282548.2:c.158+17104A>G
NM_001282549.2:c.353A>G
NP_000456.2:p.Asn118Ser
NP_001269472.1:p.Asn99Ser
NP_001269478.1:p.Asn118Ser
LRG_297t1:c.353A>G
LRG_297:g.22404A>G
LRG_297p1:p.Asn118Ser
NC_000002.11:g.215657032T>C
NG_012047.2:g.22397A>G
NM_000465.2:c.353A>G
NM_000465.3:c.353A>G
NR_104216.2:n.467A>G
p.N118S

Protein change:

N118S

Links:

dbSNP: rs142864491

NCBI 1000 Genomes Browser:

rs142864491

Molecular consequence:

NM_001282545.2:c.215+4753A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001282548.2:c.158+17104A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000465.4:c.353A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001282543.2:c.296A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001282549.2:c.353A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_104216.2:n.467A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Familial cancer of breast
Synonyms:: Breast cancer, familial; Hereditary breast cancer
Identifiers:: MONDO: MONDO:0016419; MedGen: C0346153; OMIM: 114480

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000545661	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 21, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30925164, 28492532
SCV000785042	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (Mar 24, 2017)	unknown	clinical testing	Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf, Citation Link,
SCV000837982	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Uncertain significance (Jul 2, 2018)	unknown	clinical testing	Citation Link,
SCV004019278	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Likely benign (Feb 24, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

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

Citations

PubMed

Functional analysis of BARD1 missense variants in homology-directed repair and damage sensitivity.

Adamovich AI, Banerjee T, Wingo M, Duncan K, Ning J, Martins Rodrigues F, Huang KL, Lee C, Chen F, Ding L, Parvin JD.

PLoS Genet. 2019 Mar;15(3):e1008049. doi: 10.1371/journal.pgen.1008049.

PubMed [citation]

PMID:: 30925164
PMCID:: PMC6457558

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000545661.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 118 of the BARD1 protein (p.Asn118Ser). This variant is present in population databases (rs142864491, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with BARD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 127738). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect BARD1 function (PMID: 30925164). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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 Counsyl, SCV000785042.2

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mendelics, SCV000837982.2

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV004019278.1

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

Description

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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