NM_007294.4(BRCA1):c.5165C>A (p.Ser1722Tyr) AND Hereditary cancer-predisposing syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Mar 5, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000582258.5

Allele description [Variation Report for NM_007294.4(BRCA1):c.5165C>A (p.Ser1722Tyr)]

NM_007294.4(BRCA1):c.5165C>A (p.Ser1722Tyr)

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.5165C>A (p.Ser1722Tyr)
HGVS:
  • NC_000017.11:g.43063361G>T
  • NG_005905.2:g.154623C>A
  • NM_007294.4:c.5165C>AMANE SELECT
  • NM_007297.4:c.5024C>A
  • NM_007298.3:c.1853C>A
  • NM_007299.4:c.1853C>A
  • NM_007300.4:c.5228C>A
  • NP_009225.1:p.Ser1722Tyr
  • NP_009225.1:p.Ser1722Tyr
  • NP_009228.2:p.Ser1675Tyr
  • NP_009229.2:p.Ser618Tyr
  • NP_009230.2:p.Ser618Tyr
  • NP_009231.2:p.Ser1743Tyr
  • LRG_292t1:c.5165C>A
  • LRG_292:g.154623C>A
  • LRG_292p1:p.Ser1722Tyr
  • NC_000017.10:g.41215378G>T
  • NM_007294.3:c.5165C>A
  • NR_027676.2:n.5342C>A
Protein change:
S1675Y
Links:
dbSNP: rs80357104
NCBI 1000 Genomes Browser:
rs80357104
Molecular consequence:
  • NM_007294.4:c.5165C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007297.4:c.5024C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007298.3:c.1853C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007299.4:c.1853C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007300.4:c.5228C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_027676.2:n.5342C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Functional consequence:
function_uncertain_variant [Sequence Ontology: SO:0002220] - Comment(s)
Observations:
1

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
SCV000688544Color Health, Inccriteria provided, single submitter
Uncertain significance
(Jun 22, 2019)
germlineclinical testing

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

SCV001185556Ambry Geneticscriteria provided, single submitter
Likely pathogenic
(Mar 5, 2020)
germlineclinical testing

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Structure of BRCA1-BRCT/Abraxas Complex Reveals Phosphorylation-Dependent BRCT Dimerization at DNA Damage Sites.

Wu Q, Paul A, Su D, Mehmood S, Foo TK, Ochi T, Bunting EL, Xia B, Robinson CV, Wang B, Blundell TL.

Mol Cell. 2016 Feb 4;61(3):434-448. doi: 10.1016/j.molcel.2015.12.017. Epub 2016 Jan 14.

PubMed [citation]
PMID:
26778126
PMCID:
PMC4747905
See all PubMed Citations (4)

Details of each submission

From Color Health, Inc, SCV000688544.3

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

From Ambry Genetics, SCV001185556.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (3)

Description

The p.S1722Y variant (also known as c.5165C>A), located in coding exon 17 of the BRCA1 gene, results from a C to A substitution at nucleotide position 5165. The serine at codon 1722 is replaced by tyrosine, an amino acid with dissimilar properties. One functional study found that this nucleotide substitution is predicted to have a intermediate impact on function in a high throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). In a different functional study, this variant had wildtype homologous repair activity, but also had poorly solubility due to aggregation in E coli thus was not ascertained for stability (Petitalot A et al. Mol. Cancer Res., 2019 01;17:54-69). A close match alteration, BRCA2 p.S1722F, is considered a pathogenic mutation with a severe impact on protein stability, also had intermediate activity in the high throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Based on internal structural analysis, this variant is more disruptive than known pathogenic variants, including BRCA2 p.S1722F (Wu Q et al. Mol. Cell, 2016 Feb;61:434-448). In addition, this variant segregated with breast and ovarian cancer in one family tested at this laboratory (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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

Last Updated: Dec 4, 2021

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