Submissions for variant NM_000038.6(APC):c.1825G>A (p.Val609Ile)

gnomAD frequency: 0.00096  dbSNP: rs147863331

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000679049	SCV000148979	likely benign	not provided	2021-06-01	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23159591, 25980754, 22585170, 26802149, 27978560, 28135145, 28873162, 26667234)
Ambry Genetics	RCV000115070	SCV000186859	likely benign	Hereditary cancer-predisposing syndrome	2018-09-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000198802	SCV000253992	benign	Familial adenomatous polyposis 1	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000198802	SCV000488039	uncertain significance	Familial adenomatous polyposis 1	2015-12-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115070	SCV000681488	likely benign	Hereditary cancer-predisposing syndrome	2016-04-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679049	SCV000805373	likely benign	not provided	2017-06-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000417366	SCV000918451	benign	not specified	2018-11-19	criteria provided, single submitter	clinical testing	Variant summary: APC c.1825G>A (p.Val609Ile) results in a conservative amino acid change located in the Armadillo of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 277028 control chromosomes. The observed variant frequency is approximately 4.19 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 benign. c.1825G>A has been reported in the literature in individuals affected with colorectal cancer, Lynch syndrome, breast cancer, and other unspecified phenotypes (Kerr_2013, Liang_2016, Pearlman_2016, Yurgelun_2017, Yurgelun_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. Co-occurrences with other pathogenic variant(s) have been reported (TP53 c.742C>T, p.Arg248Trp; APC c.3927_3931delAAAGA, p.Glu1309fsX4, internal testing), providing supporting evidence for a benign role. 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. Based on the evidence outlined above, the variant was classified as benign.
Sema4, Sema4	RCV000115070	SCV002530476	likely benign	Hereditary cancer-predisposing syndrome	2020-11-03	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000198802	SCV004018801	likely benign	Familial adenomatous polyposis 1	2023-02-22	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679049	SCV004221795	benign	not provided	2022-08-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000679049	SCV005041968	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	APC: BS1
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353927	SCV000591092	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The APC p.Val609Ile variant was identified in 5 of 8718 proband chromosomes (frequency: 0.0006) from individuals or families with colorectal cancer (Kerr 2012, Pearlman 2017, Yurgelun 2015, Yurgelun 2017). The variant was also identified in dbSNP (ID: rs147863331) as "With other allele", ClinVar (classified as likely benign by Invitae, GeneDx, Ambry Genetics and three other submitters; as uncertain significance by Counsyl), and in LOVD 3.0 (1x as VUS). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 83 of 277028 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the African population in 83 of 24034 chromosomes (freq: 0.003), while the variant was not observed in the Other, Latino, European, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The variant was identified in our laboratory with a co-occurring pathogenic APC variant (c.4391_4394del, p.Glu1464Valfs*8), increasing the likelihood that the p.Val609Ile variant does not have clinical significance. The p.Val609 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.