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NM_000249.4(MLH1):c.791A>T (p.His264Leu) AND Hereditary cancer-predisposing syndrome

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
May 19, 2020
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV000130953.5

Allele description [Variation Report for NM_000249.4(MLH1):c.791A>T (p.His264Leu)]

NM_000249.4(MLH1):c.791A>T (p.His264Leu)

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.791A>T (p.His264Leu)
HGVS:
  • NC_000003.12:g.37017506A>T
  • NG_007109.2:g.29157A>T
  • NM_000249.4:c.791A>TMANE SELECT
  • NM_001167617.3:c.497A>T
  • NM_001167618.3:c.68A>T
  • NM_001167619.3:c.68A>T
  • NM_001258271.2:c.791A>T
  • NM_001258273.2:c.68A>T
  • NM_001258274.3:c.68A>T
  • NM_001354615.2:c.68A>T
  • NM_001354616.2:c.68A>T
  • NM_001354617.2:c.68A>T
  • NM_001354618.2:c.68A>T
  • NM_001354619.2:c.68A>T
  • NM_001354620.2:c.497A>T
  • NM_001354621.2:c.-139-2804A>T
  • NM_001354622.2:c.-139-2804A>T
  • NM_001354623.2:c.-139-2804A>T
  • NM_001354624.2:c.-37+2962A>T
  • NM_001354625.2:c.-37+2962A>T
  • NM_001354626.2:c.-37+2962A>T
  • NM_001354627.2:c.-37+2962A>T
  • NM_001354628.2:c.791A>T
  • NM_001354629.2:c.692A>T
  • NM_001354630.2:c.791A>T
  • NP_000240.1:p.His264Leu
  • NP_000240.1:p.His264Leu
  • NP_001161089.1:p.His166Leu
  • NP_001161090.1:p.His23Leu
  • NP_001161091.1:p.His23Leu
  • NP_001245200.1:p.His264Leu
  • NP_001245202.1:p.His23Leu
  • NP_001245203.1:p.His23Leu
  • NP_001341544.1:p.His23Leu
  • NP_001341545.1:p.His23Leu
  • NP_001341546.1:p.His23Leu
  • NP_001341547.1:p.His23Leu
  • NP_001341548.1:p.His23Leu
  • NP_001341549.1:p.His166Leu
  • NP_001341557.1:p.His264Leu
  • NP_001341558.1:p.His231Leu
  • NP_001341559.1:p.His264Leu
  • LRG_216t1:c.791A>T
  • LRG_216:g.29157A>T
  • LRG_216p1:p.His264Leu
  • NC_000003.11:g.37058997A>T
  • NM_000249.3:c.791A>T
  • p.H264L
Protein change:
H166L
Links:
dbSNP: rs63751664
NCBI 1000 Genomes Browser:
rs63751664
Molecular consequence:
  • NM_001354621.2:c.-139-2804A>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354622.2:c.-139-2804A>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354623.2:c.-139-2804A>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354624.2:c.-37+2962A>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354625.2:c.-37+2962A>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354626.2:c.-37+2962A>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354627.2:c.-37+2962A>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000249.4:c.791A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167617.3:c.497A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167618.3:c.68A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167619.3:c.68A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258271.2:c.791A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258273.2:c.68A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258274.3:c.68A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354615.2:c.68A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354616.2:c.68A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354617.2:c.68A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354618.2:c.68A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354619.2:c.68A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354620.2:c.497A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354628.2:c.791A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354629.2:c.692A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354630.2:c.791A>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000185868Ambry Genetics
criteria provided, single submitter

(Ambry Autosomal Dominant and X-Linked criteria (2/2020))		Uncertain significance
(May 19, 2020) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV001347239Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Feb 12, 2019) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

Functional analysis of rare variants in mismatch repair proteins augments results from computation-based predictive methods.

Arora S, Huwe PJ, Sikder R, Shah M, Browne AJ, Lesh R, Nicolas E, Deshpande S, Hall MJ, Dunbrack RL Jr, Golemis EA.

Cancer Biol Ther. 2017 Jul 3;18(7):519-533. doi: 10.1080/15384047.2017.1326439. Epub 2017 May 11.

PubMed [citation]
PMID:
28494185
PMCID:
PMC5639829

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Ambry Genetics, SCV000185868.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

The p.H264L variant (also known as c.791A>T), located in coding exon 10 of the MLH1 gene, results from an A to T substitution at nucleotide position 791. The histidine at codon 264 is replaced by leucine, an amino acid with similar properties. This change occurs in the first base pair of coding exon 10. A functional study including this alteration showed reduction in mRNA expression, though proficient protein expression as well as viability comparable to wild-type in response to DNA-damaging treatments (Arora S et al. Cancer Biol. Ther. 2017 Jul;18:519-533). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

From Color Diagnostics, LLC DBA Color Health, SCV001347239.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Dec 24, 2023