Submissions for variant NM_000179.3(MSH6):c.4062_4065dup (p.Leu1356fs)

dbSNP: rs1553334056

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164648	SCV000215313	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-25	criteria provided, single submitter	clinical testing	The c.4062_4065dupGACT variant is located in coding exon 10 of the MSH6 gene and results from a duplication of GACT at positions 4062-4065 causing a translational frameshift with a predicted alternate stop codon (p.L1356Dfs*4). This variant has been identified in probands whose Lynch syndrome-associated tumors were microsatellite stable (MSS) and/or demonstrated normal mismatch repair protein expression by immunohistochemistry (IHC) (Ambry internal data; Kraus C et al. Int. J. Cancer. 2015 Mar;136:E559-68). Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of MSH6, is not expected to trigger nonsense-mediated mRNA decay, and results in alteration of three amino acids and removal of the last two amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time; however, another alteration leading to premature truncation at the same position has been reported at high frequency in the Chinese population and is considered a benign polymorphism (Chan TL et al. J. Natl. Cancer Inst. 1999 Jul;91:1221-6). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000548864	SCV000624962	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu1356Aspfs*4) in the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 5 amino acid(s) of the MSH6 protein. This variant is present in population databases (rs775836476, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome, colorectal cancer, prostate cancer, and thyroid cancer (PMID: 25142776, 28765196, 29625052, 32832836). ClinVar contains an entry for this variant (Variation ID: 185259). RNA analysis performed to evaluate the impact of this premature translational stop signal 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.
Color Diagnostics, LLC DBA Color Health	RCV000164648	SCV000908444	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-06	criteria provided, single submitter	clinical testing	This variant inserts 4 nucleotides in exon 10 of the MSH6 gene, creating a frameshift and premature translation stop signal in the last coding exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein, impacting the last five amino acids. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individuals affected with colorectal cancer (PMID: 25142776), breast cancer (PMID: 31784482; doi: 10.1016/j.gim.2022.01.077), prostate cancer (PMID: 32832836), and Lynch syndrome (PMID: 28765196). This variant has been identified in 16/250986 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	RCV001193725	SCV001362782	likely benign	not specified	2019-06-20	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.4062_4065dupGACT (p.Leu1356AspfsX4) results in a frameshift, causing a premature termination codon in the last exon of the encoded protein. The variant is located 5 amino acids upstream from the termination codon, therefore it is unlikely to trigger nonsense-mediated decay (NMD), but is predicted to result in a mutant protein that replaces the last 5 amino acids. The variant allele was found at a frequency of 6.4e-05 in 250986 control chromosomes, predominantly at a frequency of 0.00043 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Though the variant, c.4062_4065dupGACT, has been reported in the literature in two affected individuals (Kraus_2015, Borras_2017), in one of these cases a microsatellite stable tumor was noted (Kraus_2015), and in the other patient a co-occurring likely pathogenic MLH1 variant (c.306G>T, p.E102D) was reported (Borras_2017). In addition, a similar frameshift variant affecting the same C-terminal amino acids (p.Leu1356Serfs*4) was also found in 11/99 Southern Chinese controls and classified as a common polymorphism (PMID 10413423). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Baylor Genetics	RCV003467301	SCV004197572	uncertain significance	Endometrial carcinoma	2023-10-26	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354554	SCV001549200	uncertain significance	Lynch syndrome		no assertion criteria provided	clinical testing	The MSH6 p.Leu1356AspfsX4 variant was identified in 1 of 304 proband chromosomes (frequency: 0.003) from German individuals or families with CRC (Kraus 2014). The variant was also identified in dbSNP (ID: rs775836476) as “NA”, ClinVar (classified as uncertain significance by Ambry Genetics), Clinvitae (1x), and in control databases in 15 of 245802 chromosomes at a frequency of 0.00006 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: South Asian in 13 of 30692 chromosomes (frequency: 0.0004), East Asian in 1 of 17226 chromosomes (frequency: 0.00006) and European Non-Finnish in 1 of 111546 chromosomes (frequency 0.000009). The variant was not identified in Genesight-COGR, Cosmic, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors Database. The p.Leu1356AspfsX4 is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1356 and leads to a premature stop codon 4 codons downstream, shortening the protein transcript by 2 amino acids. Notably, variants occurring 50 base pairs before the penultimate exon junction/in the last exon of the gene and stop codon or nonsense mutations in this region may not be subjected to nonsense mediated RNA decay, although further study would be required to validate this hypothesis and it is currently not possible to determine whether or not this might influence the severity of the disorder. 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.