ClinVar Miner

Submissions for variant NM_000038.6(APC):c.7781C>G (p.Ser2594Cys) (rs543396310)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000276968 SCV000452048 benign APC-Associated Polyposis Disorders 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae RCV000462798 SCV000562657 benign Familial adenomatous polyposis 1 2020-12-04 criteria provided, single submitter clinical testing
GeneDx RCV001712147 SCV000616639 likely benign not provided 2020-11-09 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 27354939)
Ambry Genetics RCV000566206 SCV000667328 likely benign Hereditary cancer-predisposing syndrome 2018-02-22 criteria provided, single submitter clinical testing Other data supporting benign classification;Subpopulation frequency in support of benign classification
Color Health, Inc RCV000566206 SCV000910797 benign Hereditary cancer-predisposing syndrome 2016-11-14 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000462798 SCV001552658 benign Familial adenomatous polyposis 1 no assertion criteria provided clinical testing The APC p.Ser2594Cys variant was not identified in the literature nor in Genesight-COGR, Insight Colon Cancer Gene Variant Database, and Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs543396310) “With Likely benign allele”, ClinVar (classified as benign by Clinvitae and likely benign by Illumina Clinical Services Laboratory), Clinvitae (2x), Cosmic (1x in a carcinoma of the large intestine and in control databases in 103 (2 homozygous) of 245484 chromosomes at a frequency of 0.0004 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: African in 1 of 15284 chromosomes (frequency: 0.00007), Other in 1 of 5464 chromosomes (frequency: 0.0002), European Non-Finnish in 1 of 111164 crhomosomes (frequency: 0.000009), and in South Asian in 100 (2 homozygous) of 30734 chromosomes (frequency: 0.003). The variant was also identified by our laboratory in 1 individual with polyposis, co-occurring with a pathogenic APC variant (c.509_512delATAG, p. p.Asp170ValfsX4). The p.Ser2594 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.

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