Submissions for variant NM_000249.4(MLH1):c.1876T>C (p.Phe626Leu)

gnomAD frequency: 0.00001  dbSNP: rs377241633

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000214440	SCV000274895	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-28	criteria provided, single submitter	clinical testing	The p.F626L variant (also known as c.1876T>C), located in coding exon 16 of the MLH1 gene, results from a T to C substitution at nucleotide position 1876. The phenylalanine at codon 626 is replaced by leucine, an amino acid with highly similar properties. In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). In another study, this alteration was seen in 1/732 breast cancer patients, 1/189 colorectal cancer patients and 0/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 01;148:285-295). This alteration was also identified in an individual diagnosed with colorectal cancer (Erdem HB et al. Turk J Med Sci, 2020 Apr;:). This amino acid position is highly 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	RCV000216958	SCV000279349	uncertain significance	not provided	2021-08-25	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with renal papillary cell carcinoma (Yehia 2018); This variant is associated with the following publications: (PMID: 22753075, 20533529, 12799449, 29684080, 28529006)
Invitae	RCV000462112	SCV000543608	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 626 of the MLH1 protein (p.Phe626Leu). This variant is present in population databases (rs377241633, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 231139). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function. 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.
Mendelics	RCV000708930	SCV000838027	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000214440	SCV000903142	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 626 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individuals affected with colorectal cancer (PMID 32283892, 32658311). This variant has been identified in 5/251410 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330588	SCV004037607	uncertain significance	not specified	2023-08-28	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1876T>C (p.Phe626Leu) results in a non-conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal domain (IPR032189) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251410 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1876T>C has been reported in the literature as a VUS in settings of multigene panel testing among individuals with Breast cancer (example, Guindalini_2022) and was also detected as a reportedly somatic variant along with at-least one other putatively causal somatic MSH2 variant (p.E483*) in a MSS stable colorectal and/or small intestine tumor that was positive for MLH1/MSH2/MSH6 and PMS2 by immunohistochemistry (IHC) and demonstrated a high tumor mutational burden (Kiyozumi_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been utilized in the context of this evaluation, PMID: 35264596, 33046448. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003475015	SCV004195036	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-10-23	criteria provided, single submitter	clinical testing