NM_007294.4(BRCA1):c.5416C>G (p.Pro1806Ala) AND Hereditary cancer-predisposing syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Mar 24, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000164214.3

Allele description [Variation Report for NM_007294.4(BRCA1):c.5416C>G (p.Pro1806Ala)]

NM_007294.4(BRCA1):c.5416C>G (p.Pro1806Ala)

Gene:
BRCA1:BRCA1 DNA repair associated [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17q21.31
Genomic location:
Preferred name:
NM_007294.4(BRCA1):c.5416C>G (p.Pro1806Ala)
HGVS:
  • NC_000017.11:g.43047694G>C
  • NG_005905.2:g.170290C>G
  • NM_007294.3:c.5416C>G
  • NM_007294.4:c.5416C>GMANE SELECT
  • NM_007297.4:c.5275C>G
  • NM_007298.3:c.2104C>G
  • NM_007299.4:c.2030C>G
  • NM_007300.4:c.5479C>G
  • NP_009225.1:p.Pro1806Ala
  • NP_009225.1:p.Pro1806Ala
  • NP_009228.2:p.Pro1759Ala
  • NP_009229.2:p.Pro702Ala
  • NP_009230.2:p.Pro677Arg
  • NP_009231.2:p.Pro1827Ala
  • LRG_292t1:c.5416C>G
  • LRG_292:g.170290C>G
  • LRG_292p1:p.Pro1806Ala
  • NC_000017.10:g.41199711G>C
  • NR_027676.2:n.5593C>G
  • U14680.1:n.5535C>G
  • p.P1806A
Protein change:
P1759A
Links:
dbSNP: rs80357241
NCBI 1000 Genomes Browser:
rs80357241
Molecular consequence:
  • NM_007294.3:c.5416C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007294.4:c.5416C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007297.4:c.5275C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007298.3:c.2104C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007299.4:c.2030C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007300.4:c.5479C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NR_027676.2:n.5593C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Functional consequence:
functionally_normal [Sequence Ontology: SO:0002219] - Comment(s)

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MedGen: C0027672

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000214835Ambry Geneticscriteria provided, single submitter
Likely benign
(Mar 14, 2018)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV001352269Color Health, Inccriteria provided, single submitter
Uncertain significance
(Mar 24, 2020)
germlineclinical testing

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

Description

This missense variant replaces proline with alanine at codon 1806 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional assays have shown that this variant displays comparable transcription activation activity compared to the wild-type control (PMID: 10811118, 15172985, 17308087, 20516115) and it also has been reported to be functional in a haploid cell proliferation assay (PMID: 30209399). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/251484 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

SCV001352269

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod

Citations

PubMed

Functional assay for BRCA1: mutagenesis of the COOH-terminal region reveals critical residues for transcription activation.

Hayes F, Cayanan C, Barillà D, Monteiro AN.

Cancer Res. 2000 May 1;60(9):2411-8.

PubMed [citation]
PMID:
10811118
PMCID:
PMC4893312

Determination of cancer risk associated with germ line BRCA1 missense variants by functional analysis.

Carvalho MA, Marsillac SM, Karchin R, Manoukian S, Grist S, Swaby RF, Urmenyi TP, Rondinelli E, Silva R, Gayol L, Baumbach L, Sutphen R, Pickard-Brzosowicz JL, Nathanson KL, Sali A, Goldgar D, Couch FJ, Radice P, Monteiro AN.

Cancer Res. 2007 Feb 15;67(4):1494-501.

PubMed [citation]
PMID:
17308087
PMCID:
PMC2936786
See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000214835.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (4)

Description

In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

From Color Health, Inc, SCV001352269.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 14, 2021

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