Submissions for variant NM_000249.4(MLH1):c.601G>C (p.Val201Leu)

gnomAD frequency: 0.00001  dbSNP: rs534184145

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165537	SCV000216269	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-21	criteria provided, single submitter	clinical testing	The p.V201L variant (also known as c.601G>C), located in coding exon 8 of the MLH1 gene, results from a G to C substitution at nucleotide position 601. The valine at codon 201 is replaced by leucine, an amino acid with highly similar properties. This alteration has been reported as a variant of unknown significance in a cohort of patients with pancreatic ductal adenocarcinoma (Grant RC et al. Gastroenterology, 2015 Mar;148:556-64). 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.
GeneDx	RCV000221109	SCV000279077	uncertain significance	not provided	2021-11-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history including pancreatic cancer (Grant 2015); This variant is associated with the following publications: (PMID: 22753075, 25479140)
Invitae	RCV000472998	SCV000543601	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 201 of the MLH1 protein (p.Val201Leu). This variant is present in population databases (rs534184145, gnomAD 0.0009%). This missense change has been observed in individual(s) with pancreatic cancer (PMID: 25479140). ClinVar contains an entry for this variant (Variation ID: 186017). 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%. 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.
Counsyl	RCV000663069	SCV000786136	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2018-03-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165537	SCV000911476	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-15	criteria provided, single submitter	clinical testing	This missense variant replaces valine with leucine at codon 201 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with pancreatic cancer and an individual affected with endometrial cancer (PMID: 25479140, 34994648). This variant has been identified in 1/31408 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.
Myriad Genetics, Inc.	RCV000663069	SCV004018117	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-13	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
All of Us Research Program, National Institutes of Health	RCV003995425	SCV004835304	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces valine with leucine at codon 201 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with pancreatic cancer and an individual affected with endometrial cancer (PMID: 25479140, 34994648). This variant has been identified in 1/31408 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.