NM_000249.4(MLH1):c.2131T>C (p.Ser711Pro) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 21, 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:: RCV000823517.4

Allele description [Variation Report for NM_000249.4(MLH1):c.2131T>C (p.Ser711Pro)]

NM_000249.4(MLH1):c.2131T>C (p.Ser711Pro)

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.2131T>C (p.Ser711Pro)

HGVS:

NC_000003.12:g.37050513T>C
NG_007109.2:g.62164T>C
NM_000249.4:c.2131T>CMANE SELECT
NM_001167617.3:c.1837T>C
NM_001167618.3:c.1408T>C
NM_001167619.3:c.1408T>C
NM_001258271.2:c.1924T>C
NM_001258273.2:c.1408T>C
NM_001258274.3:c.1408T>C
NM_001354615.2:c.1408T>C
NM_001354616.2:c.1408T>C
NM_001354617.2:c.1408T>C
NM_001354618.2:c.1408T>C
NM_001354619.2:c.1408T>C
NM_001354620.2:c.1837T>C
NM_001354621.2:c.1108T>C
NM_001354622.2:c.1108T>C
NM_001354623.2:c.1108T>C
NM_001354624.2:c.1057T>C
NM_001354625.2:c.1057T>C
NM_001354626.2:c.1057T>C
NM_001354627.2:c.1057T>C
NM_001354628.2:c.2038T>C
NM_001354629.2:c.2032T>C
NM_001354630.2:c.1966T>C
NP_000240.1:p.Ser711Pro
NP_000240.1:p.Ser711Pro
NP_001161089.1:p.Ser613Pro
NP_001161090.1:p.Ser470Pro
NP_001161091.1:p.Ser470Pro
NP_001245200.1:p.Ser642Pro
NP_001245202.1:p.Ser470Pro
NP_001245203.1:p.Ser470Pro
NP_001341544.1:p.Ser470Pro
NP_001341545.1:p.Ser470Pro
NP_001341546.1:p.Ser470Pro
NP_001341547.1:p.Ser470Pro
NP_001341548.1:p.Ser470Pro
NP_001341549.1:p.Ser613Pro
NP_001341550.1:p.Ser370Pro
NP_001341551.1:p.Ser370Pro
NP_001341552.1:p.Ser370Pro
NP_001341553.1:p.Ser353Pro
NP_001341554.1:p.Ser353Pro
NP_001341555.1:p.Ser353Pro
NP_001341556.1:p.Ser353Pro
NP_001341557.1:p.Ser680Pro
NP_001341558.1:p.Ser678Pro
NP_001341559.1:p.Ser656Pro
LRG_216t1:c.2131T>C
LRG_216:g.62164T>C
LRG_216p1:p.Ser711Pro
NC_000003.11:g.37092004T>C
NM_000249.3:c.2131T>C
p.S711P

Protein change:

S353P

Links:

dbSNP: rs587781342

NCBI 1000 Genomes Browser:

rs587781342

Molecular consequence:

NM_000249.4:c.2131T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.1837T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.1408T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.1408T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.1924T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.1408T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.1408T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.1408T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.1408T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.1408T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.1408T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.1408T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.1837T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.1108T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.1108T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.1108T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.1057T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.1057T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.1057T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.1057T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.2038T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.2032T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.1966T>C - 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
SCV000964378	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 21, 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

SCV000964378

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 21, 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, SCV000964378.3

#	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 proline, which is neutral and non-polar, at codon 711 of the MLH1 protein (p.Ser711Pro). 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: 140884). 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 with a negative predictive value of 95%. 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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