NM_007294.4(BRCA1):c.5152T>G (p.Trp1718Gly) AND Hereditary breast and ovarian cancer syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Apr 18, 2021)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV001050456.3

Allele description [Variation Report for NM_007294.4(BRCA1):c.5152T>G (p.Trp1718Gly)]

NM_007294.4(BRCA1):c.5152T>G (p.Trp1718Gly)

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.5152T>G (p.Trp1718Gly)
HGVS:
  • NC_000017.11:g.43063874A>C
  • NG_005905.2:g.154110T>G
  • NM_007294.4:c.5152T>GMANE SELECT
  • NM_007297.4:c.5011T>G
  • NM_007298.3:c.1840T>G
  • NM_007299.4:c.1840T>G
  • NM_007300.4:c.5215T>G
  • NP_009225.1:p.Trp1718Gly
  • NP_009225.1:p.Trp1718Gly
  • NP_009228.2:p.Trp1671Gly
  • NP_009229.2:p.Trp614Gly
  • NP_009230.2:p.Trp614Gly
  • NP_009231.2:p.Trp1739Gly
  • LRG_292t1:c.5152T>G
  • LRG_292:g.154110T>G
  • LRG_292p1:p.Trp1718Gly
  • NC_000017.10:g.41215891A>C
  • NM_007294.3:c.5152T>G
  • NR_027676.2:n.5329T>G
Protein change:
W1671G
Links:
dbSNP: rs1567769155
NCBI 1000 Genomes Browser:
rs1567769155
Molecular consequence:
  • NM_007294.4:c.5152T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007297.4:c.5011T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007298.3:c.1840T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007299.4:c.1840T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007300.4:c.5215T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NR_027676.2:n.5329T>G - 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
SCV001214564Invitaecriteria provided, single submitter
Uncertain significance
(Feb 25, 2019)
germlineclinical testing

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

SCV001623344Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Apr 18, 2021)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

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

Citations

PubMed

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

Accurate classification of BRCA1 variants with saturation genome editing.

Findlay GM, Daza RM, Martin B, Zhang MD, Leith AP, Gasperini M, Janizek JD, Huang X, Starita LM, Shendure J.

Nature. 2018 Oct;562(7726):217-222. doi: 10.1038/s41586-018-0461-z. Epub 2018 Sep 12.

PubMed [citation]
PMID:
30209399
PMCID:
PMC6181777
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV001214564.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces tryptophan with glycine at codon 1718 of the BRCA1 protein (p.Trp1718Gly). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA1-related conditions. This variant has been reported to affect BRCA1 protein function (PMID: 30209399). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001623344.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

Variant summary: BRCA1 c.5152T>G (p.Trp1718Gly) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. BRCT domain is highly conserved and known to interact with multiple phospho-proteins in facilitating the tumor suppression function of BRCA1 (Sinha_2021). Other pathogenic variants in the BRCT domain have been reported. However, a computational study utilizing molecular dynamic simulation to classify VUS in the BRCT domain of BRCA1 reported this change as tolerated (Singh_2020). This variant also alters the last nucleotide of exon 17 adjacent to the canonical splice donor site. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251212 control chromosomes. c.5152T>G has been reported in the literature in at-least one individual affected with breast cancer in a large study that used a panel of 34 putative susceptibility genes to perform sequencing on 60,466 women with breast cancer and 53,461 controls (example, Dorling_2021). These data do not allow unequivocal conclusions about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a loss of HDR activity (example, Findlay_2018). Three 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. At-least one submitter cites overlapping functional evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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

Last Updated: Dec 4, 2021

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