NM_000465.4(BARD1):c.2291T>C (p.Ile764Thr) AND Familial cancer of breast

Germline classification:: Uncertain significance (5 submissions)
Last evaluated:: Mar 15, 2024
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:: RCV000466685.23

Allele description [Variation Report for NM_000465.4(BARD1):c.2291T>C (p.Ile764Thr)]

NM_000465.4(BARD1):c.2291T>C (p.Ile764Thr)

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.2291T>C (p.Ile764Thr)

Other names:

p.I764T:ATA>ACA

HGVS:

NC_000002.12:g.214728719A>G
NG_012047.3:g.85993T>C
NM_000465.4:c.2291T>CMANE SELECT
NM_001282543.2:c.2234T>C
NM_001282545.2:c.938T>C
NM_001282548.2:c.881T>C
NM_001282549.2:c.752T>C
NP_000456.2:p.Ile764Thr
NP_001269472.1:p.Ile745Thr
NP_001269474.1:p.Ile313Thr
NP_001269477.1:p.Ile294Thr
NP_001269478.1:p.Ile251Thr
LRG_297t1:c.2291T>C
LRG_297:g.85993T>C
LRG_297p1:p.Ile764Thr
NC_000002.11:g.215593443A>G
NG_012047.2:g.85986T>C
NM_000465.2:c.2291T>C
NM_000465.3:c.2291T>C
NR_104212.2:n.2256T>C
NR_104215.2:n.2199T>C
NR_104216.2:n.1455T>C

Protein change:

I251T

Links:

dbSNP: rs587780030

NCBI 1000 Genomes Browser:

rs587780030

Molecular consequence:

NM_000465.4:c.2291T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001282543.2:c.2234T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001282545.2:c.938T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001282548.2:c.881T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001282549.2:c.752T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_104212.2:n.2256T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_104215.2:n.2199T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_104216.2:n.1455T>C - 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
SCV000545655	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 19, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25452441, 31036035, 28492532
SCV000837939	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Uncertain significance (Jul 2, 2018)	unknown	clinical testing	Citation Link,
SCV002049518	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Uncertain significance (Apr 19, 2021)	germline	clinical testing	Citation Link,
SCV002579036	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 4, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004217191	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 15, 2024)	unknown	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	1	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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer.

Couch FJ, Hart SN, Sharma P, Toland AE, Wang X, Miron P, Olson JE, Godwin AK, Pankratz VS, Olswold C, Slettedahl S, Hallberg E, Guidugli L, Davila JI, Beckmann MW, Janni W, Rack B, Ekici AB, Slamon DJ, Konstantopoulou I, Fostira F, Vratimos A, et al.

J Clin Oncol. 2015 Feb 1;33(4):304-11. doi: 10.1200/JCO.2014.57.1414. Epub 2014 Dec 1.

PubMed [citation]

PMID:: 25452441
PMCID:: PMC4302212

Germline loss-of-function variants in the BARD1 gene are associated with early-onset familial breast cancer but not ovarian cancer.

Weber-Lassalle N, Borde J, Weber-Lassalle K, Horváth J, Niederacher D, Arnold N, Kaulfuß S, Ernst C, Paul VG, Honisch E, Klaschik K, Volk AE, Kubisch C, Rapp S, Lichey N, Altmüller J, Lepkes L, Pohl-Rescigno E, Thiele H, Nürnberg P, Larsen M, Richters L, et al.

Breast Cancer Res. 2019 Apr 29;21(1):55. doi: 10.1186/s13058-019-1137-9.

PubMed [citation]

PMID:: 31036035
PMCID:: PMC6489184

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000545655.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 764 of the BARD1 protein (p.Ile764Thr). This variant is present in population databases (rs587780030, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 25452441, 31036035). ClinVar contains an entry for this variant (Variation ID: 127736). 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 disruptive. 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 Mendelics, SCV000837939.2

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV002049518.1

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

Description

The BARD1 c.2291T>C; p.Ile764Thr variant (rs587780030) is reported in the literature in individuals affected with breast cancer (Couch 2014 and Weber-Lassalle 2018). This variant is also reported in ClinVar (Variation ID: 127736) and is found in the general population with an allele frequency of 0.0012% (3/251,226 alleles) in the Genome Aggregation Database. The isoleucine at codon 764 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.438). Due to limited information, the clinical significance of the p.Ile764Thr variant is uncertain at this time.

#	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 MGZ Medical Genetics Center, SCV002579036.1

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

From Baylor Genetics, SCV004217191.2

#	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

Last Updated: Oct 20, 2024

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