Submissions for variant NM_000249.4(MLH1):c.1379A>C (p.Glu460Ala)

gnomAD frequency: 0.00007  dbSNP: rs202038499

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001354082	SCV000149368	likely benign	not provided	2021-01-04	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25648859, 19697156, 23047549, 24933000, 18547406, 21120944, 27601186, 27146957, 26845104)
Ambry Genetics	RCV000115459	SCV000184951	likely benign	Hereditary cancer-predisposing syndrome	2019-03-05	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000524234	SCV000253132	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000196112	SCV000266177	uncertain significance	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000254663	SCV000539651	uncertain significance	not specified	2016-10-26	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Variant has been reported in 2 individuals with CRC who were both compound het for other MSH2 frameshift variants that segregated in the family. It is not present in ExAC. Variant classified in ClinVar as Likely Benign by Ambry, GeneDx, Invitae, and as VUS by U Wash (1 star). Variant is in a poorly conserved region. MaxMAF = 0.04% in ExAC (high for disease prevalence).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001354082	SCV000601353	likely benign	not provided	2020-12-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115459	SCV000684741	likely benign	Hereditary cancer-predisposing syndrome	2015-11-08	criteria provided, single submitter	clinical testing
Counsyl	RCV000662461	SCV000784942	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2017-02-15	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000662461	SCV001905475	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2021-09-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115459	SCV002528645	likely benign	Hereditary cancer-predisposing syndrome	2021-10-25	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000254663	SCV002552491	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662461	SCV004018212	benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-16	criteria provided, single submitter	clinical testing	This variant is considered 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].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000254663	SCV004223420	likely benign	not specified	2023-11-07	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1379A>C (p.Glu460Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 250798 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MLH1 causing Lynch Syndrome (0.00016 vs 0.00071), allowing no conclusion about variant significance. c.1379A>C has been reported in the literature in individuals with cancer (Lagerstedt-Robinson_2016, Christensen_2008, Kansikas_2011, Delahunty_2022, Jarhelle_2019, Pal_2012, Therkildsen_2015, Svensson_2022, Jones_2015, Shirts_2016), however these report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (MSH2, Exon 8 del; MSH2, p.M663fs), providing supporting evidence for a benign role (Kansikas_2011). At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no effect on protein expression levels or repair efficiency (Christensen_2009). The following publications have been ascertained in the context of this evaluation (PMID: 25648859, 35263119, 21120944, 35430768, 25877891, 27601186, 26845104, 18547406, 31882575, 19697156, 23047549). 12 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; two submitters classified the variant as a variant of uncertain significance, while 10 submitters classified it as likely benign/benign. Based on the evidence outlined above, the variant was classified as likely benign.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354082	SCV001548610	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MLH1 p.Glu460Ala variant was identified in 6 of 2074 proband chromosomes (frequency: 0.003) from individuals or families with Lynch syndrome, colorectal cancer, oligodendroglioma or glioblastoma and was not identified in 1440 control chromosomes from healthy individuals (Christensen 2008, Lagerstedt-Robinson 2016, Therkildsen 2015). The variant was also identified in dbSNP (ID: rs202038499) as "With other allele", ClinVar (classified as likely benign by Invitae, Ambry Genetics, GeneDx, and three other submitters; and as uncertain significance by two submitters), UMD-LSDB (1x unclassified variant), and in Insight Hereditary Tumors Database (8x). The variant was not identified in COGR, Cosmic, MutDB, Zhejiang University Database, or Mismatch Repair Genes Variant Database. The variant was identified in control databases in 39 of 277072 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 38 of 126582 chromosomes (freq: 0.0003) and Finnish in 1 of 25794 chromosomes (freq: 0.00004), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, Latino, Other, or South Asian populations. The p.Glu460 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The variant has been identified in patients with co-occurring pathogenic MSH2 variants (c.1277-?_1386+?del and p.Met663fs), increasing the likelihood that the p.Glu460Ala variant does not have clinical significance (Therkildsen 2015, Kansikas 2011, Christensen 2009) In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001354082	SCV001741611	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001354082	SCV001957451	likely benign	not provided		no assertion criteria provided	clinical testing