NM_000179.3(MSH6):c.1063G>A (p.Gly355Ser) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Nov 1, 2022
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000588001.19

Allele description [Variation Report for NM_000179.3(MSH6):c.1063G>A (p.Gly355Ser)]

NM_000179.3(MSH6):c.1063G>A (p.Gly355Ser)

Gene:

MSH6:mutS homolog 6 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.1063G>A (p.Gly355Ser)

Other names:

p.G355S:GGT>AGT

HGVS:

NC_000002.12:g.47799046G>A
NG_007111.1:g.20900G>A
NM_000179.3:c.1063G>AMANE SELECT
NM_001281492.2:c.673G>A
NM_001281493.2:c.157G>A
NM_001281494.2:c.157G>A
NP_000170.1:p.Gly355Ser
NP_000170.1:p.Gly355Ser
NP_001268421.1:p.Gly225Ser
NP_001268422.1:p.Gly53Ser
NP_001268423.1:p.Gly53Ser
LRG_219t1:c.1063G>A
LRG_219:g.20900G>A
LRG_219p1:p.Gly355Ser
NC_000002.11:g.48026185G>A
NM_000179.2:c.1063G>A
p.G355S

Protein change:

G225S

Links:

dbSNP: rs587778531

NCBI 1000 Genomes Browser:

rs587778531

Molecular consequence:

NM_000179.3:c.1063G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.673G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.157G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.157G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000211273	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Dec 4, 2017)	germline	clinical testing	Citation Link,
SCV001469562	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Likely benign (Nov 1, 2022)	unknown	clinical testing	PubMed (9) [See all records that cite these PMIDs] 33471991, 32547938, 31666926, 31307542, 31360874, 33563768, 26530882, 27487738, 26467025
SCV002010120	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 3, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000211273

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Dec 4, 2017)

germline

clinical testing

Citation Link,

SCV001469562

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Likely benign
(Nov 1, 2022)

unknown

clinical testing

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

SCV002010120

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 3, 2021)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.

Breast Cancer Association Consortium., Dorling L, Carvalho S, Allen J, González-Neira A, Luccarini C, Wahlström C, Pooley KA, Parsons MT, Fortuno C, Wang Q, Bolla MK, Dennis J, Keeman R, Alonso MR, Álvarez N, Herraez B, Fernandez V, Núñez-Torres R, Osorio A, Valcich J, Li M, et al.

N Engl J Med. 2021 Feb 4;384(5):428-439. doi: 10.1056/NEJMoa1913948. Epub 2021 Jan 20.

PubMed [citation]

PMID:: 33471991
PMCID:: PMC7611105

Lynch Syndrome Germline Mutations in Breast Cancer: Next Generation Sequencing Case-Control Study of 1,263 Participants.

Nikitin AG, Chudakova DA, Enikeev RF, Sakaeva D, Druzhkov M, Shigapova LH, Brovkina OI, Shagimardanova EI, Gusev OA, Gordiev MG.

Front Oncol. 2020;10:666. doi: 10.3389/fonc.2020.00666.

PubMed [citation]

PMID:: 32547938
PMCID:: PMC7273971

See all PubMed Citations (10)

Details of each submission

From GeneDx, SCV000211273.11

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant is denoted MSH6 c.1063G>A at the cDNA level, p.Gly355Ser (G355S) at the protein level, and results in the change of a Glycine to a Serine (GGT>AGT). This variant has been reported in two related individuals with non-medullary thyroid cancer (Yu 2015), and in an Asian patient with early-onset colorectal cancer (DeRycke 2017). This variant was also observed in 1/62 healthy East Asian individuals undergoing whole genome sequencing (Bodian 2014); of note, the participants in this study were younger than 50 years old, thus the unaffected status of this individual may not be significant. MSH6 Gly355Ser was observed at an allele frequency of 0.15% (29/18,868) in individuals of East Asian ancestry in large population cohorts (Lek 2016). Since Glycine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Gly355Ser is located within the nuclear localization signals (Gassman 2011). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether MSH6 Gly355Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001469562.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden, SCV002010120.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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