NM_000465.4(BARD1):c.1028C>T (p.Thr343Ile) AND Familial cancer of breast

Germline classification:: Conflicting classifications of pathogenicity (5 submissions)
Last evaluated:: Jan 30, 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:: RCV000206115.27

Allele description [Variation Report for NM_000465.4(BARD1):c.1028C>T (p.Thr343Ile)]

NM_000465.4(BARD1):c.1028C>T (p.Thr343Ile)

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.1028C>T (p.Thr343Ile)

Other names:

p.T343I:ACC>ATC

HGVS:

NC_000002.12:g.214780846G>A
NG_012047.3:g.33866C>T
NM_000465.4:c.1028C>TMANE SELECT
NM_001282543.2:c.971C>T
NM_001282545.2:c.215+16215C>T
NM_001282548.2:c.159-28291C>T
NM_001282549.2:c.364+11451C>T
NP_000456.2:p.Thr343Ile
NP_001269472.1:p.Thr324Ile
LRG_297t1:c.1028C>T
LRG_297:g.33866C>T
LRG_297p1:p.Thr343Ile
NC_000002.11:g.215645570G>A
NG_012047.2:g.33859C>T
NM_000465.2:c.1028C>T
NM_000465.3:c.1028C>T
NR_104212.2:n.993C>T
NR_104215.2:n.936C>T
p.T343I

Protein change:

T324I

Links:

dbSNP: rs201032007

NCBI 1000 Genomes Browser:

rs201032007

Molecular consequence:

NM_001282545.2:c.215+16215C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001282548.2:c.159-28291C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001282549.2:c.364+11451C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000465.4:c.1028C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282543.2:c.971C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_104212.2:n.993C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_104215.2:n.936C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

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
SCV000259877	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 30, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 26315354, 27443514, 34646395, 35595798, 30925164, 28492532
SCV000488955	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (Jul 26, 2016)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Counsyl Autosomal Dominant Disease Classification criteria (2015), Citation Link,
SCV000837973	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Uncertain significance (Jul 2, 2018)	unknown	clinical testing	Citation Link,
SCV003806921	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 22, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004019269	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	yes	1	not provided	not provided	1	not provided	clinical testing
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

Germline multi-gene hereditary cancer panel testing in an unselected endometrial cancer cohort.

Ring KL, Bruegl AS, Allen BA, Elkin EP, Singh N, Hartman AR, Daniels MS, Broaddus RR.

Mod Pathol. 2016 Nov;29(11):1381-1389. doi: 10.1038/modpathol.2016.135. Epub 2016 Jul 22.

PubMed [citation]

PMID:: 27443514
PMCID:: PMC5541389

Identification of a novel pathogenic variant in PALB2 and BARD1 genes by a multigene sequencing panel in triple negative breast cancer in Morocco.

Laraqui A, Cavaillé M, Uhrhammer N, ElBiad O, Bidet Y, El Rhaffouli H, El Anaz H, Rahali DM, Kouach J, Guelzim K, Badaoui B, AlBouzidi A, Oukabli M, Tanz R, Sbitti Y, Ichou M, Ennibi K, Sekhsokh Y, Bignon YJ.

J Genomics. 2021;9:43-54. doi: 10.7150/jgen.61713.

PubMed [citation]

PMID:: 34646395
PMCID:: PMC8490085

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000259877.11

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 343 of the BARD1 protein (p.Thr343Ile). This variant is present in population databases (rs201032007, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer, endometrial cancer, and/or ovarian cancer (PMID: 26315354, 27443514, 34646395, 35595798). ClinVar contains an entry for this variant (Variation ID: 127712). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect BARD1 function (PMID: 30925164). 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, SCV000488955.2

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mendelics, SCV000837973.2

#	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 Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV003806921.1

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

Description

ACMG classification criteria: PM2 moderated, BP4 supporting

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

From Myriad Genetics, Inc., SCV004019269.1

#	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: Jan 19, 2025

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