Submissions for variant NM_000249.4(MLH1):c.1775G>C (p.Ser592Thr)

gnomAD frequency: 0.00001  dbSNP: rs587782621

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132004	SCV000187063	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-06	criteria provided, single submitter	clinical testing	The p.S592T variant (also known as c.1775G>C), located in coding exon 16 of the MLH1 gene, results from a G to C substitution at nucleotide position 1775. The serine at codon 592 is replaced by threonine, an amino acid with similar properties. This alteration was identified in an individual with pancreatic cancer who also had a CDKN2A gene mutation (Yang XR et al. Hum. Genet. 2016 Nov;135:1241-1249). This alteration was seen in 1/150 unselected patients with recurrent or metastatic prostate cancer (Isaacsson Velho P et al. Prostate. 2018 04;78:401-407). This amino acid position is not well 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.
Invitae	RCV000524250	SCV000254359	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 592 of the MLH1 protein (p.Ser592Thr). This variant is present in population databases (rs587782621, gnomAD 0.003%). This missense change has been observed in individual(s) with pancreatic and/or prostate cancer (PMID: 27449771, 29368341). ClinVar contains an entry for this variant (Variation ID: 142658). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MLH1 protein function with a negative predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000199682	SCV000296891	uncertain significance	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000483590	SCV000565162	uncertain significance	not provided	2023-02-16	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Observed in an individual with prostate cancer as well as an individual with pancreatic cancer who also reportedly harbored a pathogenic CDKN2A variant (Yang et al., 2016; Isaacsson Velho et al., 2018); This variant is associated with the following publications: (PMID: 30113427, 29368341, 27449771, 12799449, 20533529, 22753075)
Color Diagnostics, LLC DBA Color Health	RCV000132004	SCV000684771	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This missense variant replaces serine with threonine at codon 592 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual affected with pancreatic cancer, who also carried an unspecified CDKN2A variant (PMID: 27449771), as well as in an individual affected with prostate cancer (PMID: 29368341). This variant has been identified in 3/251258 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Counsyl	RCV000662692	SCV000785420	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2017-08-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000132004	SCV002528675	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-21	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000662692	SCV004018101	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-13	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
PreventionGenetics, part of Exact Sciences	RCV003407556	SCV004113418	uncertain significance	MLH1-related disorder	2023-06-14	criteria provided, single submitter	clinical testing	The MLH1 c.1775G>C variant is predicted to result in the amino acid substitution p.Ser592Thr. This variant has been reported in an individual with pancreatic cancer and an individual with prostate cancer (Table S4, Yang et al. 2016, PubMed ID: 27449771; Table S1, Isaacsson Velho et al. 2018. PubMed ID: 29368341). This variant is reported in 3 of ~251,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/3-37089053-G-C). It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/142658/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV000662692	SCV004195055	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-10-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000199682	SCV004843214	uncertain significance	Lynch syndrome	2023-12-15	criteria provided, single submitter	clinical testing	This missense variant replaces serine with threonine at codon 592 of the MLH1 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been observed in an individual affected with pancreatic cancer who also has an unspecified CDKN2A variant (PMID: 27449771). This variant has been identified in 3/251258 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.