NM_000249.4(MLH1):c.80G>A (p.Arg27Gln) AND Hereditary nonpolyposis colorectal neoplasms

Clinical significance:Uncertain significance (Last evaluated: Oct 12, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:

Allele description [Variation Report for NM_000249.4(MLH1):c.80G>A (p.Arg27Gln)]

NM_000249.4(MLH1):c.80G>A (p.Arg27Gln)

MLH1:mutL homolog 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000249.4(MLH1):c.80G>A (p.Arg27Gln)
  • NC_000003.12:g.36993627G>A
  • NG_007109.2:g.5278G>A
  • NG_008418.1:g.4678C>T
  • NM_000249.3:c.80G>A
  • NM_000249.4:c.80G>AMANE SELECT
  • NM_001167617.3:c.-437G>A
  • NM_001167618.3:c.-866G>A
  • NM_001167619.3:c.-779G>A
  • NM_001258271.2:c.80G>A
  • NM_001258273.2:c.-553G>A
  • NM_001258274.3:c.-1016G>A
  • NM_001354615.2:c.-547G>A
  • NM_001354616.2:c.-547G>A
  • NM_001354617.2:c.-639G>A
  • NM_001354618.2:c.-871G>A
  • NM_001354619.2:c.-995G>A
  • NM_001354620.2:c.-205G>A
  • NM_001354621.2:c.-964G>A
  • NM_001354622.2:c.-1077G>A
  • NM_001354623.2:c.-986G>A
  • NM_001354624.2:c.-747G>A
  • NM_001354625.2:c.-645G>A
  • NM_001354626.2:c.-742G>A
  • NM_001354627.2:c.-974G>A
  • NM_001354628.2:c.80G>A
  • NM_001354629.2:c.80G>A
  • NM_001354630.2:c.80G>A
  • NP_000240.1:p.Arg27Gln
  • NP_000240.1:p.Arg27Gln
  • NP_001245200.1:p.Arg27Gln
  • NP_001341557.1:p.Arg27Gln
  • NP_001341558.1:p.Arg27Gln
  • NP_001341559.1:p.Arg27Gln
  • LRG_216t1:c.80G>A
  • LRG_216:g.5278G>A
  • LRG_216p1:p.Arg27Gln
  • NC_000003.11:g.37035118G>A
Protein change:
dbSNP: rs138705565
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_001167617.3:c.-437G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167618.3:c.-866G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167619.3:c.-779G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258273.2:c.-553G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258274.3:c.-1016G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354615.2:c.-547G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354616.2:c.-547G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354617.2:c.-639G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354618.2:c.-871G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354619.2:c.-995G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354620.2:c.-205G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354621.2:c.-964G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354622.2:c.-1077G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354623.2:c.-986G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354624.2:c.-747G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354625.2:c.-645G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354626.2:c.-742G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354627.2:c.-974G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000249.3:c.80G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000249.4:c.80G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258271.2:c.80G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354628.2:c.80G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354629.2:c.80G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354630.2:c.80G>A - missense variant - [Sequence Ontology: SO:0001583]


Hereditary nonpolyposis colorectal neoplasms
MedGen: C0009405; Orphanet: 443090

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000254372Invitaecriteria provided, single submitter
Uncertain significance
(Oct 12, 2020)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing



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]

Implementation of a Systematic Tumor Screening Program for Lynch Syndrome in an Integrated Health Care Setting.

Clarke EV, Muessig KR, Zepp J, Hunter JE, Syngal S, Acheson LS, Wiesner GL, Peterson SK, Bergen KM, Shuster E, Davis JV, Schneider JL, Kauffman TL, Gilmore MJ, Reiss JA, Rope AF, Cook JE, Goddard KAB.

Fam Cancer. 2019 Jul;18(3):317-325. doi: 10.1007/s10689-019-00123-x.

PubMed [citation]
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000254372.8

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)


This sequence change replaces arginine with glutamine at codon 27 of the MLH1 protein (p.Arg27Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs138705565, ExAC 0.003%). This variant has been observed in individuals with colorectal cancer and breast cancer (PMID: 25503501, 30729418). However, in one of these individuals, a pathogenic allele was also identified in MLH1, which suggests that this c.80G>A variant may not be the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 216337). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 20, 2021

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