NM_000249.4(MLH1):c.2172_2173delinsAG (p.Arg725Gly) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 24, 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:: RCV000463195.9

Allele description [Variation Report for NM_000249.4(MLH1):c.2172_2173delinsAG (p.Arg725Gly)]

NM_000249.4(MLH1):c.2172_2173delinsAG (p.Arg725Gly)

Gene:

MLH1:mutL homolog 1 [Gene - OMIM - HGNC]

Variant type:

Indel

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.2172_2173delinsAG (p.Arg725Gly)

HGVS:

NC_000003.12:g.37050554_37050555delinsAG
NG_007109.2:g.62205_62206delinsAG
NM_000249.4:c.2172_2173delinsAGMANE SELECT
NM_001167617.3:c.1878_1879delinsAG
NM_001167618.3:c.1449_1450delinsAG
NM_001167619.3:c.1449_1450delinsAG
NM_001258271.2:c.1965_1966delinsAG
NM_001258273.2:c.1449_1450delinsAG
NM_001258274.3:c.1449_1450delinsAG
NM_001354615.2:c.1449_1450delinsAG
NM_001354616.2:c.1449_1450delinsAG
NM_001354617.2:c.1449_1450delinsAG
NM_001354618.2:c.1449_1450delinsAG
NM_001354619.2:c.1449_1450delinsAG
NM_001354620.2:c.1878_1879delinsAG
NM_001354621.2:c.1149_1150delinsAG
NM_001354622.2:c.1149_1150delinsAG
NM_001354623.2:c.1149_1150delinsAG
NM_001354624.2:c.1098_1099delinsAG
NM_001354625.2:c.1098_1099delinsAG
NM_001354626.2:c.1098_1099delinsAG
NM_001354627.2:c.1098_1099delinsAG
NM_001354628.2:c.2079_2080delinsAG
NM_001354629.2:c.2073_2074delinsAG
NM_001354630.2:c.2007_2008delinsAG
NP_000240.1:p.Arg725Gly
NP_000240.1:p.Arg725Gly
NP_001161089.1:p.Arg627Gly
NP_001161090.1:p.Arg484Gly
NP_001161091.1:p.Arg484Gly
NP_001245200.1:p.Arg656Gly
NP_001245202.1:p.Arg484Gly
NP_001245203.1:p.Arg484Gly
NP_001341544.1:p.Arg484Gly
NP_001341545.1:p.Arg484Gly
NP_001341546.1:p.Arg484Gly
NP_001341547.1:p.Arg484Gly
NP_001341548.1:p.Arg484Gly
NP_001341549.1:p.Arg627Gly
NP_001341550.1:p.Arg384Gly
NP_001341551.1:p.Arg384Gly
NP_001341552.1:p.Arg384Gly
NP_001341553.1:p.Arg367Gly
NP_001341554.1:p.Arg367Gly
NP_001341555.1:p.Arg367Gly
NP_001341556.1:p.Arg367Gly
NP_001341557.1:p.Arg694Gly
NP_001341558.1:p.Arg692Gly
NP_001341559.1:p.Arg670Gly
LRG_216t1:c.2172_2173delinsAG
LRG_216:g.62205_62206delinsAG
LRG_216p1:p.Arg725Gly
NC_000003.11:g.37092045_37092046delinsAG
NM_000249.3:c.2172_2173delGCinsAG
NM_000249.3:c.2172_2173delinsAG
p.R725G

Protein change:

R367G

Links:

dbSNP: rs786203433

NCBI 1000 Genomes Browser:

rs786203433

Molecular consequence:

NM_000249.4:c.2172_2173delinsAG - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.1878_1879delinsAG - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.1449_1450delinsAG - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.1449_1450delinsAG - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.1965_1966delinsAG - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.1449_1450delinsAG - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.1449_1450delinsAG - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.1449_1450delinsAG - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.1449_1450delinsAG - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.1449_1450delinsAG - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.1449_1450delinsAG - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.1449_1450delinsAG - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.1878_1879delinsAG - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.1149_1150delinsAG - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.1149_1150delinsAG - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.1149_1150delinsAG - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.1098_1099delinsAG - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.1098_1099delinsAG - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.1098_1099delinsAG - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.1098_1099delinsAG - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.2079_2080delinsAG - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.2073_2074delinsAG - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.2007_2008delinsAG - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary nonpolyposis colorectal neoplasms
Identifiers:: MeSH: D003123; MedGen: C0009405

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LOC127884633 [Homo sapiens]
LOC127884633 [Homo sapiens]
Gene ID:127884633

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000543545	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 24, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25503501, 34347074, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000543545

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 24, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer.

Maxwell KN, Wubbenhorst B, D'Andrea K, Garman B, Long JM, Powers J, Rathbun K, Stopfer JE, Zhu J, Bradbury AR, Simon MS, DeMichele A, Domchek SM, Nathanson KL.

Genet Med. 2015 Aug;17(8):630-8. doi: 10.1038/gim.2014.176. Epub 2014 Dec 11.

PubMed [citation]

PMID:: 25503501
PMCID:: PMC4465412

Germline Alterations in Patients With IBD-associated Colorectal Cancer.

Biscaglia G, Latiano A, Castellana S, Fontana R, Gentile A, Latiano T, Corritore G, Panza A, Nardella M, Martino G, Bossa F, Perri F, Mazza T, Andriulli A, Palmieri O.

Inflamm Bowel Dis. 2022 Mar 2;28(3):447-454. doi: 10.1093/ibd/izab195.

PubMed [citation]

PMID:: 34347074

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000543545.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 725 of the MLH1 protein (p.Arg725Gly). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This missense change has been observed in individual(s) with breast and colon cancer (PMID: 25503501, 34347074). ClinVar contains an entry for this variant (Variation ID: 187049). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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