ClinVar Genomic variation as it relates to human health

Variant summary: MSH6 c.3974_3976delAGA (p.Lys1325del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant was absent in 247744 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3974_3976delAGA has been reported in the literature as a homozygous variant in a patient with colorectal cancer (CRC) who fulfilled the Bethesda guidelines, reporting consanguineous family, no family history of CRC and no associated features of CMMRD (Carneiro_2015, Rossi_2017), a patient with suspected Lynch syndrome (LS), MSI-High tumor, tumor with LOH for MSH2, first degree relatives with Lynch syndrome associated tumors (Jansen_2016), and a patient with breast cancer undergoing multigene cancer panel testing (Tung_2016). 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. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as uncertain significance. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.

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.

The frequency of this variant in the general population, 0.0000066 (1/152000 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with colorectal cancer (PMID: 26437257 (2015), breast cancer (PMID: 26976419 (2016), and Lynch Syndrome (PMID: 28874130 (2017)). It has also been reported as a somatic variant in tumor specimens from individuals with Lynch Syndrome (PMID: 27300758 (2016), 26648449 (2016)). Based on the available information, we are unable to determine the clinical significance of this variant.

This variant causes the in-frame deletion of lysine 1325 in the MSH6 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a homozygous carrier affected with colorectal and lung cancer, who has a sister affected with cancer of the bile duct and has no family history of colorectal cancer (PMID: 26437257). This variant also has been detected in an individual affected with breast cancer (PMID: 26976419). This variant has not been identified 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.

The c.3974_3976delAGA variant (also known as p.K1325del) is located in coding exon 9 of the MSH6 gene. This variant results from an in-frame AGA deletion at nucleotide positions 3974 to 3976. This results in the in-frame deletion of a lysine at codon 1325. This alteration has been reported in a homozygous state in an individual diagnosed with colorectal cancer at age 41 and lung cancer at age 44. This individual's family history is also significant for consanguineous parents and a sister who died of cholangiocarcinoma at 44 years old. Authors also question the relevance and penetrance of this alteration as no other cases of colorectal cancers had been described for this family (Carneiro da Silva F et al. PLoS ONE. 2015 Oct;10:e0139753). This alteration has also been reported in one family from a cohort of Latin American families suspected of Lynch syndrome (Rossi BM et al. BMC Cancer 2017 Sep;17(1):623), and in a cohort of 488 patients with stages I to III breast cancer who were tested with a 25-gene panel test (Tung N et al. J. Clin. Oncol. 2016 May;34:1460-8). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

In-frame deletion of one amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; Observed in the homozygous state in an individual with consanguineous parents and colorectal cancer, whose personal history was not suggestive of constitutional mismatch repair deficiency (CMMR-D) and family history was not suggestive of Lynch syndrome (Carneiro da Silva et al., 2015); Located in the critical ATPase domain and MSH2 binding site (Kariola et al., 2002; Warren et al., 2007; Kansikas et al., 2011); This variant is associated with the following publications: (PMID: 27300758, 28874130, 26648449, 17531815, 21120944, 12019211, 26976419, 26437257)

This variant causes the in-frame deletion of lysine 1325 in the MSH6 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a homozygous carrier affected with colorectal and lung cancer, who has a sister affected with cancer of the bile duct but no family history of colorectal cancer (PMID: 26437257). This variant also has been detected in an individual affected with breast cancer (PMID: 26976419). This variant has not been identified 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.

This variant, c.3974_3976del, results in the deletion of 1 amino acid(s) of the MSH6 protein (p.Lys1325del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with breast, ovarian, endometrial, and/or colorectal cancer (PMID: 26437257, 26648449, 26976419). ClinVar contains an entry for this variant (Variation ID: 89494). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.

The MSH6 p.Lys1325del variant was identified in 2 of 1208 proband chromosomes (frequency: 0.002) from Brazilian and American individuals or families with suspected Lynch syndrome or breast cancer (Carneiro da Silva_2015_26437257, Tung_2016_26976419). One proband with suspected Lynch Syndrome was homozygous for the variant (parents had a consanguineous marriage), developed CRC at 41 years and had a sister diagnosed with colangiocarcinoma (Carneiro da Silva_2015_26437257). The variant was also identified in dbSNP (ID: rs587779300) “With Uncertain significance allele”, ClinVar (classified as uncertain significance, reviewed by an expert panel (2013); submitters: InSIGHT, Ambry Genetics, Counsyl, Invitae, GeneDx, Quest Diagnostics Nichols Institute San Juan Capistrano), Clinvitae (4x), Cosmic (1x in a carcinoma of the female genital tract), Insight Colon Cancer Gene Variant Database (1x as Class 3), Zhejiang Colon Cancer Database, and Insight Hereditary Tumors Database (1x); and was not identified in GeneInsight-COGR, MutDB, UMD-LSDB, Mismatch Repair Genes Variant Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). This variant is an in-frame deletion resulting in the removal of a lysine (lys) residue at codon 1325; the impact of this alteration on MSH6 protein function is not known. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.

The MSH6 c.3974_3976delAGA variant is predicted to result in an in-frame deletion (p.Lys1325del). This variant has been reported in the homozygous state in an individual who developed colon cancer (Carneiro da Silva et al. 2015. PubMed ID: 26437257). This variant has also been reported in a family and an unrelated individual with suspected Lynch syndrome (Rossi et al. 2017. PubMed ID: 28874130; Jansen et al. 2016. PubMed ID: 27300758) and in an individual with breast cancer (Table A2, Tung et al. 2016. PubMed ID: 26976419). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been interpreted as uncertain in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/89494). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.