NM_000179.2(MSH6):c.3537C>G (p.Ala1179=) AND Hereditary cancer-predisposing syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Sep 16, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000165194.2

Allele description [Variation Report for NM_000179.2(MSH6):c.3537C>G (p.Ala1179=)]

NM_000179.2(MSH6):c.3537C>G (p.Ala1179=)

Gene:
MSH6:mutS homolog 6 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2p16.3
Genomic location:
Preferred name:
NM_000179.2(MSH6):c.3537C>G (p.Ala1179=)
HGVS:
  • NC_000002.12:g.47805008C>G
  • NG_007111.1:g.26862C>G
  • NG_008397.1:g.105668G>C
  • NM_000179.2:c.3537C>G
  • NM_001281492.1:c.3147C>G
  • NM_001281493.1:c.2631C>G
  • NM_001281494.1:c.2631C>G
  • NP_000170.1:p.Ala1179=
  • NP_001268421.1:p.Ala1049=
  • NP_001268422.1:p.Ala877=
  • NP_001268423.1:p.Ala877=
  • LRG_219t1:c.3537C>G
  • LRG_219:g.26862C>G
  • LRG_219p1:p.Ala1179=
  • NC_000002.11:g.48032147C>G
  • p.A1179A
Links:
dbSNP: rs200120044
NCBI 1000 Genomes Browser:
rs200120044
Molecular consequence:
  • NM_000179.2:c.3537C>G - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_001281492.1:c.3147C>G - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_001281493.1:c.2631C>G - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_001281494.1:c.2631C>G - synonymous variant - [Sequence Ontology: SO:0001819]
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
SCV000215906Ambry Geneticscriteria provided, single submitter
Likely benign
(Aug 1, 2014)
germlineclinical testing

Citation Link,

SCV001354177Color Health, Inccriteria provided, single submitter
Uncertain significance
(Sep 16, 2019)
germlineclinical testing

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

Description

This variant causes a C>G nucleotide substitution in exon 6 of the MSH6 gene. Splice site prediction tools suggest that this variant activates a cryptic splice donor site located 24 nucleotide upstream of the reference splice site. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 10/251186 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.

SCV001354177

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

Details of each submission

From Ambry Genetics, SCV000215906.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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

From Color Health, Inc, SCV001354177.1

#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: Feb 3, 2021

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