Submissions for variant NM_000249.4(MLH1):c.1597del (p.Cys533fs)

dbSNP: rs1559575107

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000690221	SCV000817900	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-09-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys533Valfs*2) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 21642682). ClinVar contains an entry for this variant (Variation ID: 569561). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780424	SCV000917667	likely pathogenic	Lynch syndrome	2018-12-21	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1597delT (p.Cys533ValfsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.1769T>G (p.Leu590X), c.1772_1775delATAG (p.Asp591fsX24), c.2084C>A (p.Ser695X)). The variant was absent in 246050 control chromosomes (gnomAD). c.1597delT has been reported in the literature in a family affected with Lynch Syndrome (Bonadona_2011). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001186208	SCV001352559	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 14 of the MLH1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Myriad Genetics, Inc.	RCV003453440	SCV004186529	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-20	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.