NM_000179.3(MSH6):c.2314C>T (p.Arg772Trp) AND not provided

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Mar 27, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000218399.35

Allele description [Variation Report for NM_000179.3(MSH6):c.2314C>T (p.Arg772Trp)]

NM_000179.3(MSH6):c.2314C>T (p.Arg772Trp)

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.2314C>T (p.Arg772Trp)

HGVS:

NC_000002.12:g.47800297C>T
NG_007111.1:g.22151C>T
NM_000179.3:c.2314C>TMANE SELECT
NM_001281492.2:c.1924C>T
NM_001281493.2:c.1408C>T
NM_001281494.2:c.1408C>T
NP_000170.1:p.Arg772Trp
NP_000170.1:p.Arg772Trp
NP_001268421.1:p.Arg642Trp
NP_001268422.1:p.Arg470Trp
NP_001268423.1:p.Arg470Trp
LRG_219t1:c.2314C>T
LRG_219:g.22151C>T
LRG_219p1:p.Arg772Trp
NC_000002.11:g.48027436C>T
NM_000179.2:c.2314C>T
P52701:p.Arg772Trp
p.R772W

Protein change:

R470W

Links:

UniProtKB: P52701#VAR_043958; dbSNP: rs63750138

NCBI 1000 Genomes Browser:

rs63750138

Molecular consequence:

NM_000179.3:c.2314C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.1924C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.1408C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.1408C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000279102	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Mar 27, 2024)	germline	clinical testing	Citation Link,
SCV000691930	Mayo Clinic Laboratories, Mayo Clinic	no assertion criteria provided	Pathogenic	unknown	clinical testing
SCV001250448	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Sep 1, 2023)	germline	clinical testing	Citation Link,
SCV001470348	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Oct 8, 2021)	unknown	clinical testing	PubMed (13) [See all records that cite these PMIDs] 26274037, 25307252, 28449805, 30128536, 32849802, 32338768, 30322717, 24323032, 12732731, 23621914, 14974087, 18176851, 26467025
SCV002023525	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 14, 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	yes	4	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	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

Management of Acute Myeloblastic Leukemia in a Child With Biallelic Mismatch Repair Deficiency.

Elhasid R, Dvir R, Rosenfeld Keidar H, Ben Shachar S, Bitan M, Solar I, Durno C, Aronson M, Malkin D, Hawkins C, Bouffet E, Tabori U; BMMRD Consortium..

J Pediatr Hematol Oncol. 2015 Nov;37(8):e490-3. doi: 10.1097/MPH.0000000000000415.

PubMed [citation]

PMID:: 26274037

The gastrointestinal manifestation of constitutional mismatch repair deficiency syndrome: from a single adenoma to polyposis-like phenotype and early onset cancer.

Levi Z, Kariv R, Barnes-Kedar I, Goldberg Y, Half E, Morgentern S, Eli B, Baris HN, Vilkin A, Belfer RG, Niv Y, Elhasid R, Dvir R, Abu-Freha N, Cohen S.

Clin Genet. 2015 Nov;88(5):474-8. doi: 10.1111/cge.12518. Epub 2014 Nov 10.

PubMed [citation]

PMID:: 25307252

See all PubMed Citations (14)

Details of each submission

From GeneDx, SCV000279102.10

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

Description

Published functional studies demonstrate a damaging effect: deficient mismatch repair activity (PMID: 32849802); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24323032, 29345684, 30212499, 30322717, 12732731, 18176851, 14974087, 26333163, 26274037, 25307252, 28449805, 28514183, 30128536, 27498913, 23621914, 30166433, 17531815, 21120944, 32338768, 28888541, 36293153, 35451682, 29922827, 31391288, 34445333, 33804961, 31965077, 32849802)

#	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 Mayo Clinic Laboratories, Mayo Clinic, SCV000691930.1

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

#	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 CeGaT Center for Human Genetics Tuebingen, SCV001250448.25

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	not provided

Description

MSH6: PS4, PM1, PM2, PP3, PS3:Supporting

#	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		4	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001470348.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

The frequency of this variant in the general population, 0.000008 (2/251130 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with colorectal, breast, ovarian, endometrial, and prostate cancer (PMIDs: 32338768 (2020), 30128536 (2018), 30322717 (2018), 28449805 (2017), 24323032 (2014), 14974087 (2004)). It has also been reported in the homozygous state in three children with CMMRD (PMIDs: 26274037 (2015), 25307252 (2015)). Additionally, a functional study indicated this variant has significantly reduced DNA mismatch repair activity in vitro, and the variant was characterized as being pathogenic based on multifactorial analysis (PMID: 32849802 (2020)). Based on the available information, this variant is classified as pathogenic.

#	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 Revvity Omics, Revvity, SCV002023525.3

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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