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NM_000249.4(MLH1):c.649C>T (p.Arg217Cys) AND Carcinoma of colon

Germline classification:
Likely benign (1 submission)
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
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:
RCV001354844.9

Allele description [Variation Report for NM_000249.4(MLH1):c.649C>T (p.Arg217Cys)]

NM_000249.4(MLH1):c.649C>T (p.Arg217Cys)

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.649C>T (p.Arg217Cys)
Other names:
p.R217C:CGC>TGC
HGVS:
  • NC_000003.12:g.37012071C>T
  • NG_007109.2:g.23722C>T
  • NM_000249.4:c.649C>TMANE SELECT
  • NM_001167617.3:c.355C>T
  • NM_001167618.3:c.-75C>T
  • NM_001167619.3:c.-75C>T
  • NM_001258271.2:c.649C>T
  • NM_001258273.2:c.-75C>T
  • NM_001258274.3:c.-75C>T
  • NM_001354615.2:c.-75C>T
  • NM_001354616.2:c.-75C>T
  • NM_001354617.2:c.-75C>T
  • NM_001354618.2:c.-75C>T
  • NM_001354619.2:c.-75C>T
  • NM_001354620.2:c.355C>T
  • NM_001354621.2:c.-168C>T
  • NM_001354622.2:c.-281C>T
  • NM_001354623.2:c.-281C>T
  • NM_001354624.2:c.-178C>T
  • NM_001354625.2:c.-178C>T
  • NM_001354626.2:c.-178C>T
  • NM_001354627.2:c.-178C>T
  • NM_001354628.2:c.649C>T
  • NM_001354629.2:c.550C>T
  • NM_001354630.2:c.649C>T
  • NP_000240.1:p.Arg217Cys
  • NP_000240.1:p.Arg217Cys
  • NP_001161089.1:p.Arg119Cys
  • NP_001245200.1:p.Arg217Cys
  • NP_001341549.1:p.Arg119Cys
  • NP_001341557.1:p.Arg217Cys
  • NP_001341558.1:p.Arg184Cys
  • NP_001341559.1:p.Arg217Cys
  • LRG_216t1:c.649C>T
  • LRG_216:g.23722C>T
  • LRG_216p1:p.Arg217Cys
  • NC_000003.11:g.37053562C>T
  • NM_000249.3:c.649C>T
  • P40692:p.Arg217Cys
  • p.R217C
Protein change:
R119C
Links:
UniProtKB: P40692#VAR_004449; dbSNP: rs4986984
NCBI 1000 Genomes Browser:
rs4986984
Molecular consequence:
  • NM_001167618.3:c.-75C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167619.3:c.-75C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258273.2:c.-75C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258274.3:c.-75C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354615.2:c.-75C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354616.2:c.-75C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354617.2:c.-75C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354618.2:c.-75C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354619.2:c.-75C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354621.2:c.-168C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354622.2:c.-281C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354623.2:c.-281C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354624.2:c.-178C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354625.2:c.-178C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354626.2:c.-178C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354627.2:c.-178C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000249.4:c.649C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167617.3:c.355C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258271.2:c.649C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354620.2:c.355C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354628.2:c.649C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354629.2:c.550C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354630.2:c.649C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Carcinoma of colon (CRC)
Synonyms:
Colonic carcinoma; Colon carcinoma
Identifiers:
MONDO: MONDO:0002032; MedGen: C0699790

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001549555Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria provided
Likely benignunknownclinical testing

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyes1not providednot providednot providednot providedclinical testing

Details of each submission

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001549555.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

The MLH1 p.Arg217Cys variant was identified in 12 of 656 proband chromosomes (frequency: 0.02) from individuals or families with Extramammary Paget disease or sporadic colorectal cancer and was present in 8 of 1260 control chromosomes (frequency: 0.006) from healthy individuals (Kang 2016, Peng 2015). The variant was also identified in dbSNP (ID: rs4986984) as "With other allele”, ClinVar (classified as benign by Color; as likely benign by Invitae, GeneDx, Ambry Genetics and one clinical laboratory; as uncertain significance by two clinical laboratories), Cosmic (4x in Skin or bone tissue), MutDB , UMD-LSDB (2x as neutral), Zhejiang University Database, Mismatch Repair Genes Variant Database, and in Insight Hereditary Tumors (42x as uncertain) databases. The variant was not identified in COGR database. The variant was identified in control databases in 91 of 276864 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 2 of 126374 chromosomes (freq: 0.00002), East Asian in 83 of 18868 chromosomes (freq: 0.004), and South Asian in 6 of 30782 chromosomes (freq: 0.0002), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, and Finnish, populations. The p.Arg217 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Several functional studies identified the variant might affect the MMR process at different levels and might have functional relation to gastrointestinal cancer. The variant showed variable levels of MMR activity (50%, 64.8%, or 81.3%) compare to WT however overall the studies concluded that although efficiency of MMR is slightly reduced it is still proficient (Kang 2016, Lucci-Cordisco 2006, Fan 2007, Takahashi 2007, Trojan 2002). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot provided1not providednot providednot provided

Last Updated: Nov 3, 2024