NM_000465.4(BARD1):c.1127C>T (p.Ser376Leu) AND Familial cancer of breast

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jan 27, 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:: RCV000199235.15

Allele description [Variation Report for NM_000465.4(BARD1):c.1127C>T (p.Ser376Leu)]

NM_000465.4(BARD1):c.1127C>T (p.Ser376Leu)

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.1127C>T (p.Ser376Leu)

HGVS:

NC_000002.12:g.214780747G>A
NG_012047.3:g.33965C>T
NM_000465.4:c.1127C>TMANE SELECT
NM_001282543.2:c.1070C>T
NM_001282545.2:c.215+16314C>T
NM_001282548.2:c.159-28192C>T
NM_001282549.2:c.364+11550C>T
NP_000456.2:p.Ser376Leu
NP_001269472.1:p.Ser357Leu
LRG_297t1:c.1127C>T
LRG_297:g.33965C>T
LRG_297p1:p.Ser376Leu
NC_000002.11:g.215645471G>A
NG_012047.2:g.33958C>T
NM_000465.2:c.1127C>T
NM_000465.3:c.1127C>T
NR_104212.2:n.1092C>T
NR_104215.2:n.1035C>T
p.S376L

Protein change:

S357L

Links:

dbSNP: rs587782333

NCBI 1000 Genomes Browser:

rs587782333

Molecular consequence:

NM_001282545.2:c.215+16314C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001282548.2:c.159-28192C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001282549.2:c.364+11550C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000465.4:c.1127C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282543.2:c.1070C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_104212.2:n.1092C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_104215.2:n.1035C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Familial cancer of breast
Synonyms:: Breast cancer, familial
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
SCV000254565	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 27, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31159747, 28492532
SCV002580148	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 7, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004228576	GenomeConnect - Invitae Patient Insights Network	no classification provided	not provided	unknown	phenotyping only

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000254565

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 27, 2024)

germline

clinical testing

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

SCV002580148

MGZ Medical Genetics Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 7, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004228576

GenomeConnect - Invitae Patient Insights Network

no classification provided

not provided

unknown

phenotyping only

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	1	not provided	not provided	1	not provided	phenotyping only
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

Citations

PubMed

Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations.

Tsaousis GN, Papadopoulou E, Apessos A, Agiannitopoulos K, Pepe G, Kampouri S, Diamantopoulos N, Floros T, Iosifidou R, Katopodi O, Koumarianou A, Markopoulos C, Papazisis K, Venizelos V, Xanthakis I, Xepapadakis G, Banu E, Eniu DT, Negru S, Stanculeanu DL, Ungureanu A, Ozmen V, et al.

BMC Cancer. 2019 Jun 3;19(1):535. doi: 10.1186/s12885-019-5756-4.

PubMed [citation]

PMID:: 31159747
PMCID:: PMC6547505

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000254565.12

#	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 serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 376 of the BARD1 protein (p.Ser376Leu). This variant is present in population databases (rs587782333, gnomAD 0.02%). This missense change has been observed in individual(s) with hereditary cancer (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 142247). 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 leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 MGZ Medical Genetics Center, SCV002580148.1

#	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 GenomeConnect - Invitae Patient Insights Network, SCV004228576.1

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

Description

Variant interpreted as Uncertain significance and reported on 05-30-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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

Last Updated: May 7, 2024

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