NM_007294.4(BRCA1):c.5291T>C (p.Leu1764Pro) AND Hereditary breast and ovarian cancer syndrome

Clinical significance:Pathogenic (Last evaluated: Mar 3, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000588744.2

Allele description [Variation Report for NM_007294.4(BRCA1):c.5291T>C (p.Leu1764Pro)]

NM_007294.4(BRCA1):c.5291T>C (p.Leu1764Pro)

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.5291T>C (p.Leu1764Pro)
Other names:
5410T>C
HGVS:
  • NC_000017.11:g.43051104A>G
  • NG_005905.2:g.166880T>C
  • NM_007294.3:c.5291T>C
  • NM_007294.4:c.5291T>CMANE SELECT
  • NM_007297.4:c.5150T>C
  • NM_007298.3:c.1979T>C
  • NM_007299.4:c.1979T>C
  • NM_007300.4:c.5354T>C
  • NP_009225.1:p.Leu1764Pro
  • NP_009225.1:p.Leu1764Pro
  • NP_009228.2:p.Leu1717Pro
  • NP_009229.2:p.Leu660Pro
  • NP_009230.2:p.Leu660Pro
  • NP_009231.2:p.Leu1785Pro
  • LRG_292t1:c.5291T>C
  • LRG_292:g.166880T>C
  • LRG_292p1:p.Leu1764Pro
  • NC_000017.10:g.41203121A>G
  • NR_027676.2:n.5468T>C
  • P38398:p.Leu1764Pro
  • U14680.1:n.5410T>C
Protein change:
L1717P
Links:
BRCA1-HCI: BRCA1_00049; UniProtKB: P38398#VAR_063908; dbSNP: rs80357281
NCBI 1000 Genomes Browser:
rs80357281
Molecular consequence:
  • NM_007294.3:c.5291T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007294.4:c.5291T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007297.4:c.5150T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007298.3:c.1979T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007299.4:c.1979T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007300.4:c.5354T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NR_027676.2:n.5468T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Functional consequence:
functionally_abnormal [Sequence Ontology: SO:0002218] - Comment(s)

Condition(s)

Name:
Hereditary breast and ovarian cancer syndrome (HBOC)
Synonyms:
Hereditary breast and ovarian cancer; Hereditary breast and ovarian cancer syndrome (HBOC)
Identifiers:
MONDO: MONDO:0003582; MeSH: D061325; MedGen: C0677776; Orphanet: 145; OMIM: PS604370

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000699234Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Jan 31, 2017)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV001578892Invitaecriteria provided, single submitter
Pathogenic
(Mar 3, 2020)
germlineclinical testing

PubMed (14)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Application of embryonic lethal or other obvious phenotypes to characterize the clinical significance of genetic variants found in trans with known deleterious mutations.

Judkins T, Hendrickson BC, Deffenbaugh AM, Eliason K, Leclair B, Norton MJ, Ward BE, Pruss D, Scholl T.

Cancer Res. 2005 Nov 1;65(21):10096-103.

PubMed [citation]
PMID:
16267036

Clinically applicable models to characterize BRCA1 and BRCA2 variants of uncertain significance.

Spearman AD, Sweet K, Zhou XP, McLennan J, Couch FJ, Toland AE.

J Clin Oncol. 2008 Nov 20;26(33):5393-400. doi: 10.1200/JCO.2008.17.8228. Epub 2008 Sep 29. Erratum in: J Clin Oncol. 2009 May 10;27(14):2415.

PubMed [citation]
PMID:
18824701
PMCID:
PMC2651073
See all PubMed Citations (15)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000699234.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

Variant summary: The BRCA1 c.5291T>C (p.Leu1764Pro) variant located in the BRCT domain (via InterPro) involves the alteration of a conserved nucleotide, which 5/5 in silico tools predict a damaging outcome. Multiple functional studies have been performed that support these predictions. The variant of interest has not been observed in controls (ExAC, 1000 Gs, or ESP) and has been reported in multiple affected individuals via publications and databases. The variant of interest has been indicated to cause fold destabilization. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001578892.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (14)

Description

This sequence change replaces leucine with proline at codon 1764 of the BRCA1 protein (p.Leu1764Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 18824701, 29446198, 30257646, 26022348), and has also been observed to segregate with disease in an affected family (Invitae). ClinVar contains an entry for this variant (Variation ID: 55510). This variant has been reported to affect BRCA1 protein function (PMID: 17305420, 27272900, 23867111, 20516115, 17308087, 20378548, 30209399). Based on multifactorial likelihood algorithms using genetic data, this variant has been determined to have a high probability of being pathogenic (PMID: 17924331, 21990134). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 6, 2021

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