NM_003000.2(SDHB):c.269G>A (p.Arg90Gln) AND bilateral breast cancer

Clinical significance:Uncertain significance (Last evaluated: Jul 22, 2020)

Review status:(0/4) 0 stars out of maximum of 4 stars

no assertion criteria provided

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001004837.4

Allele description [Variation Report for NM_003000.2(SDHB):c.269G>A (p.Arg90Gln)]

NM_003000.2(SDHB):c.269G>A (p.Arg90Gln)

Gene:
SDHB:succinate dehydrogenase complex iron sulfur subunit B [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1p36.13
Genomic location:
Preferred name:
NM_003000.2(SDHB):c.269G>A (p.Arg90Gln)
HGVS:
  • NC_000001.11:g.17033077C>T
  • NG_012340.1:g.26094G>A
  • NM_003000.2:c.269G>A
  • NP_002991.2:p.Arg90Gln
  • LRG_316t1:c.269G>A
  • LRG_316:g.26094G>A
  • LRG_316p1:p.Arg90Gln
  • NC_000001.10:g.17359572C>T
Protein change:
R90Q
Links:
dbSNP: rs570278423
NCBI 1000 Genomes Browser:
rs570278423
Molecular consequence:
  • NM_003000.2:c.269G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
bilateral breast cancer
Identifiers:
MedGen: CN235586

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000987258Center of Medical Genetics and Primary Health Careno assertion criteria providedUncertain significance
(Jul 22, 2020)
germlineresearch

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot providednot providednot providedresearch

Details of each submission

From Center of Medical Genetics and Primary Health Care, SCV000987258.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
11not providednot providedresearchnot provided

Description

ACMG Guidelines 2015 criteria This variant is in exon 3 of the SDHB gene in the Fer2_3 domain (F42-147Y aa); it is involved in electron transfer activity, iron-sulfur cluster binding. This missense change has been shown to reduce but not entirely abolish SDHB enzymatic activity (PMID: 23175444) (PS3 Pathogenic Very Strong). This variant has been reported as pathogenic in paraganglioma (Panizzaet al., 2013). This variant is in a hotspot of 10 pathogenic missense, nonsense, and frameshift variants (source ClinVar) (PM1 Pathogenic Moderate). There is a known pathogenic null (terminating) variant (i.e., c.268C>T (p.Arg90Ter) at the same amino acid residue which also suggests that this region is a mutational hotspot (PS1 Pathogenic Strong). The allele count in GnomAD exomes and GnomAD genomes are 2 and 1, respectively, which are less the threshold 5 for dominant gene SDHB (PM2 Pathogenic Moderate). 11 pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT versus no benign predictions support its deleterious effect (PP3 Pathogenic Supporting). This variant is reported in ClinVar as a likely pathogenic variant or a VUS. In this study this variant was found in a 46-year-old female with bilateral breast cancer and no reported family history of cancer. Based on the evidence provided above, we classified this variant as a Variant of Unknown Significance.

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

Last Updated: Oct 8, 2021

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