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NM_000249.4(MLH1):c.226G>A (p.Val76Ile) AND Malignant tumor of breast

Germline classification:
Uncertain significance (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:
RCV001358259.4

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:
Malignant tumor of breast
Synonyms:
Malignant breast neoplasm; Cancer breast
Identifiers:
MONDO: MONDO:0007254; MedGen: C0006142

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001553941Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria provided
Uncertain significanceunknownclinical testing

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyesnot providednot 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), SCV001553941.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

MLH1, EXON3, c.226G>A, p.Val76Ile, Heterozygous, Uncertain SignificancernThe MLH1 p.Val76Ile variant was identified in 1 of 976 proband chromosomes (frequency: 0.001) from American individuals or families with breast cancer (Tung 2016). The variant was identified in dbSNP (ID: rs878853788) as “With Uncertain significance allele”, ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx and 2 other submitters), and UMD-LSDB (4x classified as UV). The variant was identified in control databases in 4 of 246184 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017), observed in the European Non-Finnish population in 4 of 111652 chromosomes (freq: 0.00004); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The p.Val76 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the Ile variant to the protein; this information is not very predictive of 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. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. Assessment Date: 2019/07/15. References (PMIDs): 26976419.

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

Last Updated: Sep 29, 2024