Submissions for variant NM_000249.4(MLH1):c.506C>T (p.Pro169Leu)

gnomAD frequency: 0.00001  dbSNP: rs63750834

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218502	SCV000277501	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-15	criteria provided, single submitter	clinical testing	The p.P169L variant (also known as c.506C>T), located in coding exon 6 of the MLH1 gene, results from a C to T substitution at nucleotide position 506. The proline at codon 169 is replaced by leucine, an amino acid with similar properties. This alteration was identified in a cohort of Iranian patients whose personal and family cancer history meets the Amsterdam criteria (Salehi M et al. J Sci I Iran. 2009; 20(1):7-12). This variant was reportedly detected in conjunction (phase unknown) with a pathogenic mutation in MLH1 in a 35-year-old male with mixed proximal gastric cancer (Bacani J et al. J Mol Diagn. 2005 Oct;7:465-77). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000524304	SCV000543524	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 169 of the MLH1 protein (p.Pro169Leu). This variant is present in population databases (rs63750834, gnomAD 0.0009%). This missense change has been observed in individual(s) with suspected Lynch syndrome (PMID: 31391288). ClinVar contains an entry for this variant (Variation ID: 90251). An algorithm developed specifically for the MLH1 gene suggests that this missense change is likely to be deleterious (PMID: 26333163). Studies have shown this missense change is associated with skipping of exon 6, but one or more of the resulting mRNA isoform(s) may be naturally occurring (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.
Color Diagnostics, LLC DBA Color Health	RCV000218502	SCV001342529	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-18	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 169 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 reported in trans with a pathogenic MLH1 variant in an individual affected with gastric cancer (PMID: 16237216) and in a suspected hereditary nonpolyposis colorectal cancer family (Salehi, 2008). This variant has been identified in 1/251430 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.
GeneDx	RCV003441740	SCV004167716	uncertain significance	not provided	2023-07-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Observed in a patient with mixed proximal gastric cancer with deficient MLH1 by IHC, who also harbored a pathogenic MLH1 variant (PMID: 16237216); This variant is associated with the following publications: (PMID: 26333163, 32027066, 33471991, 22753075, 16237216)
All of Us Research Program, National Institutes of Health	RCV003997132	SCV004835294	uncertain significance	Lynch syndrome	2023-10-23	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 169 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in trans with a pathogenic MLH1 variant in an individual affected with gastric cancer (PMID: 16237216) and a suspected hereditary nonpolyposis colorectal cancer family (https://jsciences.ut.ac.ir/article_31909.html). This variant has been identified in 1/251430 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.