rs63750767
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000179.3(MSH6):c.3939_3957dupTCAAAAGGGACATAGAAAA(p.Ala1320SerfsTer5) variant causes a frameshift, stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,474 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000179.3 frameshift, stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00000658 AC: 1AN: 152042Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 249986Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135216
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461432Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3AN XY: 727018
GnomAD4 genome 0.00000658 AC: 1AN: 152042Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74266
ClinVar
Submissions by phenotype
Lynch syndrome Pathogenic:5
Coding sequence variation resulting in a stop codon -
Variant summary: MSH6 c.3939_3957dup19 (p.Ala1320SerfsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 249800 control chromosomes. c.3939_3957dup19 has been reported in the literature in multiple individuals affected with Lynch Syndrome (Goodfellow_2003, Barnetson_2006, Chong_2009, Baglietto_2009, Kerr_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
The p.Ala1320fs variant in MSH6 has been reported in at least 10 individuals with MSH6-associated cancers, 1 individual with breast cancer, and 1 individual with prostate cancer (Barneston 2006, Chong 2009, Goodfellow 2003, Hampel 2008, Kerr 2016, Nowak 2017, Shirts 2016, Susswein 2015, Tung 2015, Yurgelun 2015). It also segregated with disease in one family (Buttin 2004). Tumors from many of these individuals demonstrated microsatellite instability and/or loss of MSH6 expression via IHC (Buttin 2004, Barneston 2006, Kerr 2016). This variant has also been reported in ClinVar (Variation ID 89486) and has been identified in 1/110290 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs763673818). The p.Ala1320fs variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1320 and leads to a premature termination codon 5 amino acids downstream. This termination codon occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Truncating variants downstream of this variant have been reported in individuals with Lynch syndrome. In addition, this variant was classified as pathogenic on Sept. 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000108169.2). In summary, this variant is pathogenic. ACMG/AMP Criteria applied: PVS1; PM2; PS4_Moderate; PP1; PP4. -
The c.3939_3957dup (p.Ala1320Serfs*5) variant in the MSH6 gene is located on the exon 9 and is predicted to cause reading frame shift that introduces a premature translation termination codon (p.Ala1320Serfs*5), resulting in an absent or disrupted protein product. The variant has been identified in multiple individuals with Lynch syndrome-associated cancers (PMID: 27456091, 25980754, 26552419, 18809606, 19459153, 25186627). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 30376427, 18269114). The variant is reported in ClinVar as pathogenic (ID: 89486) and reviewed by the expert panel. The variant is rare in the general population according to gnomAD (1/249986). Therefore, the c.3939_3957dup (p.Ala1320Serfs*5) variant of MSH6 has been classified as pathogenic. -
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not provided Pathogenic:5
PP4, PP5, PM2_moderate, PS4_moderate, PVS1_strong -
The MSH6 c.3939_3957dup; p.Ala1320SerfsTer5 variant (rs63750767), has been described in the literature in multiple individuals with Lynch syndrome (Carter 2018, Chong 2009, Goodfellow 2003, Kerr 2016). This variant is also reported in ClinVar (Variation ID: 89486). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant creates a frameshift by duplicating 19 nucleotides, so is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered pathogenic. References: Carter NJ et al. Germline pathogenic variants identified in women with ovarian tumors. Gynecol Oncol. 2018 Dec;151(3):481-488. PMID: 30322717. Chong G et al. High frequency of exon deletions and putative founder effects in French Canadian Lynch syndrome families. Hum Mutat. 2009; 30(8):E797-812. Goodfellow PJ et al. Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers. Proc Natl Acad Sci U S A. 2003; 100(10):5908-13. Kerr L et al. A cohort analysis of men with a family history of BRCA1/2 and Lynch mutations for prostate cancer. BMC Cancer. 2016 Jul 25;16:529. PMID: 27456091. -
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The MSH6 c.3939_3957dup (p.Ala1320Serfs*5) variant alters the translational reading frame of the MSH6 mRNA and causes the premature termination of MSH6 protein synthesis. This variant has been reported in the published literature in several individuals and families affected with a Lynch syndrome associated cancer including colorectal cancer (PMIDs: 18809606 (2008), 19459153 (2009), 25980754 (2015), 26552419 (2015), 26845104 (2016), 27456091 (2016), 28135145 (2017), 30729418 (2019), 31997046 (2020)), endometrial/ovarian cancer (PMIDs: 12732731 (2003), 26552419 (2015), 26681312 (2015), 32809219 (2020)), breast cancer (PMID: 25186627 (2015)), pancreatic cancer (PMID: 29922827 (2018)), and prostate cancer (PMIDs: 27456091 (2016), 30337059 (2019)). The frequency of this variant in the general population, 0.000004 (1/249986 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Frameshift variant predicted to result in protein truncation for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 18809606, 12732731, 25980754, 15952900, 19459153, 16807412, 26681312, 27456091, 27863258, 24100870, 21155762, 17531815, 28135145, 26845104, 26552419, 25186627, 16464007, 20028993, 30322717, 32719484, 34086170, 27535533) -
Hereditary cancer-predisposing syndrome Pathogenic:3
The c.3939_3957dup19 (p.A1320Sfs*5) alteration, located in exon 9 (coding exon 9) of the MSH6 gene, consists of a duplication of TCAAAAGGGACATAGAAAA at position 3939, causing a translational frameshift with a predicted alternate stop codon after 5 amino acids. This alteration occurs at the 3' terminus of theMSH6 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 3.01% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was detected in a French-Canadian family meeting Amsterdam II criteria for Lynch syndrome. The proband had MSH6-deficient endometrial cancer diagnosed at age 50 and a strong family history of colon, kidney, uterine, and cervical cancers (Chong, 2009). It has also been identified in a patient who was diagnosed with endometrial cancer at age 47 (Goodfellow, 2003), a male diagnosed with an MSI-H cecal tumor at age 54 (Hampel, 2008), and in a proband with prostate cancer whose tumor showed loss of MSH6 on IHC (Kerr, 2016). Based on the available evidence, this alteration is classified as pathogenic. -
This variant inserts 19 nucleotides in exon 9 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Lynch syndrome (PMID: 16807412, 19459153, 27456091), colorectal cancer (PMID: 18809606, 26845104) and endometrial and/or ovarian cancer (PMID: 26552419, 26681312). This variant has been identified in 1/249986 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
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Lynch syndrome 5 Pathogenic:1
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Carcinoma of colon Pathogenic:1
The MSH6 p.Ala1320SerfsX5 variant was identified in 5 of 1892 proband chromosomes (frequency: 0.003) from American, French Canadian and Scottish individuals or families with endometrial or colon cancer (Goodfellow 2015, Goodfellow 2003, Barnetson 2006, Chong 2009). The variant was also identified in a patient with endometrial/ovarian cancer through NGS cancer panel testing of over 10,000 consecutive cases referred for cancer testing (Susswein 2015). Buttin et al. (2004) investigated the expressivity and penetrance of pathogenic MSH6 variants (this duplication variant included) seen in endometrial cancer probands and found there is an increased cancer risk with these mutations (tumour spectrum not defined), the penetrance could be as high as 58%, and, cancer is later age onset compared to MSH2/MLH1 mutations. The variant was also identified in dbSNP (ID: rs763673818), Clinvitae database (classification pathogenic), “Mismatch Repair Genes Variant Database”, InSiGHT Colon Cancer Gene Variant Database (LOVD), and the ClinVar database (classification pathogenic, reviewed by an expert panel, submitters: InSIGHT, Ambry Genetics, GeneDx, Mayo Clinic). The c.3939_3957dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1320 and leads to a premature stop codon 5 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH6 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -
Mismatch repair cancer syndrome 3 Pathogenic:1
PVS1, PS3_Moderate, PM2; no PS4 due to this case being apparently homozygous for recessive disorder -
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
This sequence change creates a premature translational stop signal (p.Ala1320Serfs*5) in the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 41 amino acid(s) of the MSH6 protein. This variant is present in population databases (rs763673818, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer, endometrial and ovarian cancer, and/or Lynch syndrome (PMID: 18809606, 19459153, 25186627, 25980754, 26552419, 26681312, 26845104, 27456091). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH6 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MSH6 testing. ClinVar contains an entry for this variant (Variation ID: 89486). This variant disrupts a region of the MSH6 protein in which other variant(s) (p.Ala1320Glufs*6) have been determined to be pathogenic (PMID: 21155762). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Endometrial carcinoma Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at