NM_000249.4(MLH1):c.508A>G (p.Ser170Gly) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jul 29, 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:: RCV000629906.6

Allele description [Variation Report for NM_000249.4(MLH1):c.508A>G (p.Ser170Gly)]

NM_000249.4(MLH1):c.508A>G (p.Ser170Gly)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.508A>G (p.Ser170Gly)

HGVS:

NC_000003.12:g.37008868A>G
NG_007109.2:g.20519A>G
NM_000249.4:c.508A>GMANE SELECT
NM_001167617.3:c.214A>G
NM_001167618.3:c.-216A>G
NM_001167619.3:c.-179+1805A>G
NM_001258271.2:c.508A>G
NM_001258273.2:c.-216A>G
NM_001258274.3:c.-216A>G
NM_001354615.2:c.-179+1805A>G
NM_001354616.2:c.-179+1805A>G
NM_001354617.2:c.-216A>G
NM_001354618.2:c.-216A>G
NM_001354619.2:c.-216A>G
NM_001354620.2:c.214A>G
NM_001354621.2:c.-309A>G
NM_001354622.2:c.-422A>G
NM_001354623.2:c.-422A>G
NM_001354624.2:c.-319A>G
NM_001354625.2:c.-282+1805A>G
NM_001354626.2:c.-319A>G
NM_001354627.2:c.-319A>G
NM_001354628.2:c.508A>G
NM_001354629.2:c.409A>G
NM_001354630.2:c.508A>G
NP_000240.1:p.Ser170Gly
NP_000240.1:p.Ser170Gly
NP_001161089.1:p.Ser72Gly
NP_001245200.1:p.Ser170Gly
NP_001341549.1:p.Ser72Gly
NP_001341557.1:p.Ser170Gly
NP_001341558.1:p.Ser137Gly
NP_001341559.1:p.Ser170Gly
LRG_216t1:c.508A>G
LRG_216:g.20519A>G
LRG_216p1:p.Ser170Gly
NC_000003.11:g.37050359A>G
NM_000249.3:c.508A>G

Protein change:

S137G

Links:

dbSNP: rs1287294691

NCBI 1000 Genomes Browser:

rs1287294691

Molecular consequence:

NM_001167618.3:c.-216A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-216A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-216A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-216A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-216A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-216A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-309A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-422A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-422A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-319A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-319A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-319A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-179+1805A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354615.2:c.-179+1805A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354616.2:c.-179+1805A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354625.2:c.-282+1805A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.508A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.214A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.508A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.214A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.508A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.409A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.508A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000750862	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 29, 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

SCV000750862

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 29, 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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000750862.5

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

Description

This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 170 of the MLH1 protein (p.Ser170Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 483587). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MLH1 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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

ClinVar

Relating variation to medicine