NM_000249.4(MLH1):c.226G>A (p.Val76Ile) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 24, 2024
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:: RCV000233829.13

Allele description [Variation Report for NM_000249.4(MLH1):c.226G>A (p.Val76Ile)]

NM_000249.4(MLH1):c.226G>A (p.Val76Ile)

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.226G>A (p.Val76Ile)

HGVS:

NC_000003.12:g.37000973G>A
NG_007109.2:g.12624G>A
NM_000249.4:c.226G>AMANE SELECT
NM_001167617.3:c.-64G>A
NM_001167618.3:c.-498G>A
NM_001167619.3:c.-406G>A
NM_001258271.2:c.226G>A
NM_001258273.2:c.-498G>A
NM_001258274.3:c.-498G>A
NM_001354615.2:c.-401G>A
NM_001354616.2:c.-406G>A
NM_001354617.2:c.-498G>A
NM_001354618.2:c.-498G>A
NM_001354619.2:c.-498G>A
NM_001354620.2:c.-64G>A
NM_001354621.2:c.-591G>A
NM_001354622.2:c.-704G>A
NM_001354623.2:c.-704G>A
NM_001354624.2:c.-601G>A
NM_001354625.2:c.-504G>A
NM_001354626.2:c.-601G>A
NM_001354627.2:c.-601G>A
NM_001354628.2:c.226G>A
NM_001354629.2:c.208-3428G>A
NM_001354630.2:c.226G>A
NP_000240.1:p.Val76Ile
NP_000240.1:p.Val76Ile
NP_001245200.1:p.Val76Ile
NP_001341557.1:p.Val76Ile
NP_001341559.1:p.Val76Ile
LRG_216t1:c.226G>A
LRG_216:g.12624G>A
LRG_216p1:p.Val76Ile
NC_000003.11:g.37042464G>A
NM_000249.3:c.226G>A

Protein change:

V76I

Links:

dbSNP: rs878853788

NCBI 1000 Genomes Browser:

rs878853788

Molecular consequence:

NM_001167617.3:c.-64G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-498G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-406G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-498G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-498G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-401G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-406G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-498G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-498G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-498G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-64G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-591G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-704G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-704G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-601G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-504G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-601G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-601G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354629.2:c.208-3428G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.226G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.226G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.226G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.226G>A - 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
SCV000284056	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 24, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26976419, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000284056

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 24, 2024)

germline

clinical testing

PubMed (2)
[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

Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer.

Tung N, Lin NU, Kidd J, Allen BA, Singh N, Wenstrup RJ, Hartman AR, Winer EP, Garber JE.

J Clin Oncol. 2016 May 1;34(13):1460-8. doi: 10.1200/JCO.2015.65.0747. Epub 2016 Mar 14.

PubMed [citation]

PMID:: 26976419
PMCID:: PMC4872307

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, SCV000284056.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 76 of the MLH1 protein (p.Val76Ile). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer (PMID: 26976419). ClinVar contains an entry for this variant (Variation ID: 237335). 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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