NM_000465.4(BARD1):c.2291T>C (p.Ile764Thr) AND not specified

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jul 3, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001532967.3

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]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001748791	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Jul 3, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25452441, 31036035 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001748791

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Jul 3, 2021)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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

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

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001748791.1

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

Description

Variant summary: BARD1 c.2291T>C (p.Ile764Thr) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251226 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2291T>C has been reported in the literature in cases as well control individuals affected with Breast Cancer (example, Couch_2015, Weber-Lasalle_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as 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

Last Updated: Oct 20, 2024

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