NM_000465.4(BARD1):c.841C>T (p.Pro281Ser) AND Familial cancer of breast

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Mar 5, 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:: RCV000226615.19

Allele description [Variation Report for NM_000465.4(BARD1):c.841C>T (p.Pro281Ser)]

NM_000465.4(BARD1):c.841C>T (p.Pro281Ser)

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.841C>T (p.Pro281Ser)

Other names:

p.P281S:CCA>TCA

HGVS:

NC_000002.12:g.214781033G>A
NG_012047.3:g.33679C>T
NM_000465.4:c.841C>TMANE SELECT
NM_001282543.2:c.784C>T
NM_001282545.2:c.215+16028C>T
NM_001282548.2:c.158+28379C>T
NM_001282549.2:c.364+11264C>T
NP_000456.2:p.Pro281Ser
NP_001269472.1:p.Pro262Ser
LRG_297t1:c.841C>T
LRG_297:g.33679C>T
LRG_297p1:p.Pro281Ser
NC_000002.11:g.215645757G>A
NG_012047.2:g.33672C>T
NM_000465.2:c.841C>T
NM_000465.3:c.841C>T
NR_104212.2:n.806C>T
NR_104215.2:n.749C>T

Protein change:

P262S

Links:

dbSNP: rs200059956

NCBI 1000 Genomes Browser:

rs200059956

Molecular consequence:

NM_001282545.2:c.215+16028C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001282548.2:c.158+28379C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001282549.2:c.364+11264C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000465.4:c.841C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282543.2:c.784C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_104212.2:n.806C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_104215.2:n.749C>T - 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
SCV000284981	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 16, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 25980754, 26979419, 27978560, 33606809, 34250417, 28492532
SCV000786120	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (Feb 28, 2018)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26976419, 25980754, 27978560 Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf, Citation Link,
SCV000837975	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Uncertain significance (Jul 2, 2018)	unknown	clinical testing	Citation Link,
SCV004019265	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,
SCV004214995	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 5, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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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

HIV Transmission Risk Behavior in a Cohort of HIV-Infected Treatment-Naïve Men and Women in the United States.

Landovitz RJ, Tran TT, Cohn SE, Ofotokun I, Godfrey C, Kuritzkes DR, Lennox JL, Currier JS, Ribaudo HJ.

AIDS Behav. 2016 Dec;20(12):2983-2995.

PubMed [citation]

PMID:: 26979419
PMCID:: PMC5026544

Germline molecular data in hereditary breast cancer in Brazil: Lessons from a large single-center analysis.

Sandoval RL, Leite ACR, Barbalho DM, Assad DX, Barroso R, Polidorio N, Dos Anjos CH, de Miranda AD, Ferreira ACSM, Fernandes GDS, Achatz MI.

PLoS One. 2021;16(2):e0247363. doi: 10.1371/journal.pone.0247363.

PubMed [citation]

PMID:: 33606809
PMCID:: PMC7895369

See all PubMed Citations (9)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000284981.11

#	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 proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 281 of the BARD1 protein (p.Pro281Ser). This variant is present in population databases (rs200059956, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer and colon cancer (PMID: 25980754, 26979419, 27978560, 33606809, 34250417). ClinVar contains an entry for this variant (Variation ID: 127749). 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. 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, SCV000786120.2

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

#	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, SCV000837975.2

#	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., SCV004019265.1

#	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

From Baylor Genetics, SCV004214995.2

#	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: Sep 29, 2024

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