ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5912C>G (p.Ser1971Cys) (rs754691867)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167000 SCV000217822 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-14 criteria provided, single submitter clinical testing The p.S1971C variant (also known as c.5912C>G), located in coding exon 15 of the APC gene, results from a C to G substitution at nucleotide position 5912. The serine at codon 1971 is replaced by cysteine, an amino acid with dissimilar properties. The p.S1971C alteration (designated as c.5911C>G) has been reported in a Taiwanese individual with >100 colorectal adenomas and was not reported in 250 population controls (Wei SC et al. J. Biomed. Sci. 2004;11:260-5). This alteration was also identified in an cohort of unselected probands with colorectal cancer and was listed as a variant of uncertain significance (Yurgelun MB et al. J. Clin. Oncol. 2017 Apr;35(10):1086-1095). 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.
Invitae RCV000987577 SCV000261409 likely benign Familial adenomatous polyposis 1 2020-11-17 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000455669 SCV000538306 uncertain significance not specified 2016-12-14 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: This variant has been reported in one Taiwanese individual with FAP. It is present in gnomAD with a Max MAF of 0.11% (22/18910 East Asian alleles - frequency too high for disease). This variant is classified in ClinVar with 2 stars as VUS by Ambry and Invitae.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000455669 SCV000600122 benign not specified 2019-11-29 criteria provided, single submitter clinical testing
Color Health, Inc RCV000167000 SCV000681769 uncertain significance Hereditary cancer-predisposing syndrome 2021-01-20 criteria provided, single submitter clinical testing This missense variant replaces serine with cysteine at codon 1971 of the APC 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 assays have not been performed for this variant. This variant has been observed in individuals affected with colorectal cancer (PMID: 28135145) and suspected of familial adenomatous polyposis (PMID: 14966376). This variant has also been identified in 22/282164 chromosomes (22/19920 East Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). In summary, this is a variant of unknown impact on function that has been observed in affected individuals as well as in the general population. 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 RCV000455669 SCV000918490 likely benign not specified 2018-09-07 criteria provided, single submitter clinical testing Variant summary: APC c.5912C>G (p.Ser1971Cys) results in a non-conservative amino acid change in 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 8e-05 in 276666 control chromosomes, predominantly at a frequency of 0.0012 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 16.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.5912C>G has been reported in the literature in East Asian individuals affected with Familial Adenomatous Polyposis and colorectal cancer (Wei_2004, Yurgelun_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. 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 without evidence for independent evaluation, all with classifications of VUS except for one likely benign classification. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000987577 SCV001136927 uncertain significance Familial adenomatous polyposis 1 2019-05-28 criteria provided, single submitter clinical testing
3DMed Clinical Laboratory Inc RCV000677738 SCV000803894 uncertain significance Colorectal cancer 2017-05-25 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358361 SCV001554069 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The APC p.Ser1971Cys variant was identified in 2 of 2128 proband chromosomes (frequency: 0.0009) from individuals or families with familial adenomatous polyposis and colorectal cancer (Yurgelun 2017, Wei 2004). The variant was identified in dbSNP (rs754691867) as “with uncertain significance allele” and ClinVar (classified as uncertain significance by Color, Ambry Genetics and 3 other submitters; and as likely benign by Invitae and Integrated Genetics). The variant was not identified in LOVD 3.0 and UMD-LSDB. The variant was identified in control databases in 22 of 276,666 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the East Asian population in 22 of 18,832 chromosomes (freq: 0.001), but not in the African, Other, Latino, European, Ashkenazi Jewish, Finnish, or South Asian populations. The p.Ser1971 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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. 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.

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