NM_000179.3(MSH6):c.1942A>G (p.Ser648Gly) AND Lynch syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Sep 4, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV004015304.2

Allele description [Variation Report for NM_000179.3(MSH6):c.1942A>G (p.Ser648Gly)]

NM_000179.3(MSH6):c.1942A>G (p.Ser648Gly)

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.1942A>G (p.Ser648Gly)

HGVS:

NC_000002.12:g.47799925A>G
NG_007111.1:g.21779A>G
NM_000179.3:c.1942A>GMANE SELECT
NM_001281492.2:c.1552A>G
NM_001281493.2:c.1036A>G
NM_001281494.2:c.1036A>G
NM_001406795.1:c.2038A>G
NM_001406796.1:c.1942A>G
NM_001406797.1:c.1645A>G
NM_001406798.1:c.1942A>G
NM_001406799.1:c.1417A>G
NM_001406800.1:c.1942A>G
NM_001406801.1:c.1645A>G
NM_001406802.1:c.2038A>G
NM_001406803.1:c.1942A>G
NM_001406804.1:c.1864A>G
NM_001406805.1:c.1645A>G
NM_001406806.1:c.1417A>G
NM_001406807.1:c.1417A>G
NM_001406808.1:c.1942A>G
NM_001406809.1:c.1942A>G
NM_001406811.1:c.1036A>G
NM_001406812.1:c.1036A>G
NM_001406813.1:c.1948A>G
NM_001406814.1:c.1036A>G
NM_001406815.1:c.1036A>G
NM_001406816.1:c.1036A>G
NM_001406817.1:c.1606+336A>G
NM_001406818.1:c.1645A>G
NM_001406819.1:c.1645A>G
NM_001406820.1:c.1645A>G
NM_001406821.1:c.1645A>G
NM_001406822.1:c.1645A>G
NM_001406823.1:c.1036A>G
NM_001406824.1:c.1645A>G
NM_001406825.1:c.1645A>G
NM_001406826.1:c.1774A>G
NM_001406827.1:c.1645A>G
NM_001406828.1:c.1645A>G
NM_001406829.1:c.1036A>G
NM_001406830.1:c.1645A>G
NM_001407362.1:c.628-741A>G
NP_000170.1:p.Ser648Gly
NP_000170.1:p.Ser648Gly
NP_001268421.1:p.Ser518Gly
NP_001268422.1:p.Ser346Gly
NP_001268423.1:p.Ser346Gly
NP_001393724.1:p.Ser680Gly
NP_001393725.1:p.Ser648Gly
NP_001393726.1:p.Ser549Gly
NP_001393727.1:p.Ser648Gly
NP_001393728.1:p.Ser473Gly
NP_001393729.1:p.Ser648Gly
NP_001393730.1:p.Ser549Gly
NP_001393731.1:p.Ser680Gly
NP_001393732.1:p.Ser648Gly
NP_001393733.1:p.Ser622Gly
NP_001393734.1:p.Ser549Gly
NP_001393735.1:p.Ser473Gly
NP_001393736.1:p.Ser473Gly
NP_001393737.1:p.Ser648Gly
NP_001393738.1:p.Ser648Gly
NP_001393740.1:p.Ser346Gly
NP_001393741.1:p.Ser346Gly
NP_001393742.1:p.Ser650Gly
NP_001393743.1:p.Ser346Gly
NP_001393744.1:p.Ser346Gly
NP_001393745.1:p.Ser346Gly
NP_001393747.1:p.Ser549Gly
NP_001393748.1:p.Ser549Gly
NP_001393749.1:p.Ser549Gly
NP_001393750.1:p.Ser549Gly
NP_001393751.1:p.Ser549Gly
NP_001393752.1:p.Ser346Gly
NP_001393753.1:p.Ser549Gly
NP_001393754.1:p.Ser549Gly
NP_001393755.1:p.Ser592Gly
NP_001393756.1:p.Ser549Gly
NP_001393757.1:p.Ser549Gly
NP_001393758.1:p.Ser346Gly
NP_001393759.1:p.Ser549Gly
LRG_219t1:c.1942A>G
LRG_219:g.21779A>G
LRG_219p1:p.Ser648Gly
NC_000002.11:g.48027064A>G
NM_000179.2:c.1942A>G
NR_176256.1:n.804A>G
NR_176257.1:n.2031A>G
NR_176258.1:n.2031A>G
NR_176259.1:n.2031A>G
NR_176261.1:n.2031A>G

Protein change:

S346G

Molecular consequence:

NM_001406817.1:c.1606+336A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001407362.1:c.628-741A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000179.3:c.1942A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.1552A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.1036A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.1036A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406795.1:c.2038A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406796.1:c.1942A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406797.1:c.1645A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406798.1:c.1942A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406799.1:c.1417A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406800.1:c.1942A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406801.1:c.1645A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406802.1:c.2038A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406803.1:c.1942A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406804.1:c.1864A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406805.1:c.1645A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406806.1:c.1417A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406807.1:c.1417A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406808.1:c.1942A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406809.1:c.1942A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406811.1:c.1036A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406812.1:c.1036A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406813.1:c.1948A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406814.1:c.1036A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406815.1:c.1036A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406816.1:c.1036A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406818.1:c.1645A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406819.1:c.1645A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406820.1:c.1645A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406821.1:c.1645A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406822.1:c.1645A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406823.1:c.1036A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406824.1:c.1645A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406825.1:c.1645A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406826.1:c.1774A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406827.1:c.1645A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406828.1:c.1645A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406829.1:c.1036A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406830.1:c.1645A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_176256.1:n.804A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176257.1:n.2031A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176258.1:n.2031A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176259.1:n.2031A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176261.1:n.2031A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Lynch syndrome
Identifiers:: MONDO: MONDO:0005835; MedGen: C4552100

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Apodemus chevrieri isolate ZY12 D-loop, partial sequence; mitochondrial
Apodemus chevrieri isolate ZY12 D-loop, partial sequence; mitochondrial
gi|1756090636|gb|MK329825.1|

Nucleotide
Chain n, Clamp protein VP6
Chain n, Clamp protein VP6
gi|2463612783|pdb|8FJK|n

Protein
Homo sapiens chromosome 22 clone p423 map 22q11, complete sequence
Homo sapiens chromosome 22 clone p423 map 22q11, complete sequence
gi|7229748|gnl|uoknor|p423|gb|AC007 8|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004830433	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Sep 4, 2023)	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

SCV004830433

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Sep 4, 2023)

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	unknown	1	not provided	not provided	108544	not provided	clinical 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 All of Us Research Program, National Institutes of Health, SCV004830433.1

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

Description

This missense variant replaces serine with glycine at codon 648 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 1/251208 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: May 7, 2024

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