APC c.3245C>G, p.(Thr1082Ser)

Reasoning

Governing framework is the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP specification for APC v2.1. Its BS1 strong rule requires a gnomAD Popmax Filtering Allele Frequency (AF) >= 0.001% (0.00001), assessed in the gnomAD v2.1.1 non-cancer dataset per instructionsToUse. In the non-cancer gnomAD v2.1 subset the variant has a non-cancer grpmax filtering AF of 3.865e-05 (0.003865%) and an exome AF of 4.6605e-05 (11/236026 alleles); the European (Finnish) population reaches 0.000119512 (0.01195%). The threshold is exceeded by roughly four-fold on the grpmax filtering AF and by more than ten-fold on the Finnish subpopulation frequency. The result is robust to dataset choice: the all-comers gnomAD v2.1 grpmax filtering AF is 3.442e-05 (0.003442%) and gnomAD v4.1 grpmax filtering AF is 7.076e-05 (0.007076%), both also above 0.001%. BS1 is therefore met at Strong. Per the VCEP rules for combining criteria, a single Benign-Strong criterion is sufficient to reach Likely Benign, but that combination step is not applied here.

Rule

GnomAD Popmax Filtering Allele Frequency (AF) >= 0.001% (0.00001). [InSiGHT APC VCEP v2.1, Benign Strong; assess in the gnomAD v2.1.1 non-cancer dataset]

Evidence considered

• Governing specification: InSiGHT APC VCEP v2.1. BS1 strength rule: 'GnomAD Popmax Filtering Allele Frequency (AF) >= 0.001% (0.00001).' instructionsToUse: 'General recommendation: Use the non-cancer dataset from gnomAD (v2.1.1)'.
• gnomAD v2.1.1 non-cancer subset: grpmax filtering AF 3.865e-05 (0.003865%); exome AC 11, AN 236026, exome AF 4.6605035e-05; highest subpopulation European (Finnish) AF 0.00011951238945103975 (0.011950%), above the 0.001% threshold.
• gnomAD v2.1 all-comers: grpmax filtering AF 3.442e-05 (0.003442%); gnomAD v4.1 all-comers: grpmax filtering AF 7.076e-05 (0.007076%). Both exceed 0.001%.
• gnomAD v3.1 non-cancer (genomes only, no exome cohort in v3.1): total AF 4.73088e-05 (7/147964 alleles, homozygotes 0), grpmax filtering AF 1.972e-05 (0.001972%) - also above the 0.001% threshold.
• Allele frequency exceeds that expected for a fully penetrant dominant colorectal polyposis syndrome, supporting BS1 at Strong.

Sources

Reasoning

Variant consequence: missense, NP_001120982.1:p.(Thr1082Ser) (NM_001127510.3:c.3245C>G), APC. The governing ClinGen InSiGHT APC VCEP specification v2.1 makes BP1 applicable to APC at Supporting strength: 'BP1 is applicable to APC with the exception of missense variants located in the first 15-amino acid repeat of the beta-catenin binding domain (codon 1021-1035).' APC is a gene in which primarily truncating (loss-of-function) variants cause familial adenomatous polyposis, which is the premise of BP1. The variant under assessment is a missense change at residue 1082, which lies outside codons 1021-1035, so the VCEP's single stated exception does not apply and BP1 remains applicable to it. The criterion is therefore met at Supporting strength (Benign Supporting). This is the only benign direction available from this group of criteria and is applied at supporting weight only; it should be combined with the other groups' benign and pathogenic evidence by the VCEP's combining rules rather than considered in isolation. Note the variant's own predicted protein effect is not benign by in silico measures (REVEL 0.293), but BP1 as specified by the VCEP rests on the gene's variant-type mechanism, not on per-variant predictor output.

Rule

APC VCEP v2.1 BP1 (Supporting): BP1 is applicable to APC with the exception of missense variants located in the first 15-amino acid repeat of the beta-catenin binding domain (codon 1021-1035).

Evidence considered

• ClinGen InSiGHT APC VCEP specification v2.1 (cspec), BP1 Supporting rule: 'BP1 is applicable to APC with the exception of missense variants located in the first 15-amino acid repeat of the beta-catenin binding domain (codon 1021-1035).'
• The variant under assessment is a missense change at residue 1082 (p.Thr1082Ser), which is outside codons 1021-1035, so the VCEP exception does not remove BP1 applicability.
• APC is a gene in which primarily truncating (loss-of-function) variants are known to cause familial adenomatous polyposis 1 (MONDO:0021056); this is the mechanism premise of BP1.
• Cancer Hotspots (hotspots) returned no statistically significant hotspot row for APC T1082, and the VCEP exception interval (codons 1021-1035) does not include residue 1082, so no hotspot/domain consideration removes BP1 applicability.

Sources

Reasoning

Variant consequence: missense, NP_001120982.1:p.(Thr1082Ser) (NM_001127510.3:c.3245C>G), APC. The governing framework is the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel specification for APC v2.1 (cspec), which is applicable and takes precedence over generic ACMG. The APC VCEP PS1 rule is: for missense variants, PS1 is met at Strong strength when the variant under assessment results in the same amino acid change as a previously established Pathogenic variant (and at Moderate strength when the comparator was classified Likely Pathogenic); the specification states that APC currently has only two Likely Pathogenic missense variants, c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg), and that no missense variant has been classified as Pathogenic based on current evidence. The variant under assessment changes residue 1082 (p.Thr1082Ser), so its amino acid change is not p.(Asn1026Ser) or p.(Ser1028Arg), and no other established (Likely) Pathogenic APC missense shares the p.Thr1082Ser change. ClinVar variation 181799 records NM_000038.6(APC):c.3245C>G (p.Thr1082Ser) as conflicting (uncertain significance in 9 clinical laboratories and likely benign in 5 clinical laboratories; review status 'criteria provided, conflicting classifications', no expert-panel submission), so the variant's own change has never been established as Pathogenic or Likely Pathogenic. Kraus et al. 2015 (PMID:25142776) reported the variant once (patient 72) and classified it as IARC class 2, 'likely not pathogenic'. No splice-relevant comparator applies because this is a missense, not a splice, variant. PS1 is therefore not met at any strength.

Rule

APC VCEP v2.1 PS1 (Strong): The previously established variant was classified as Pathogenic according to the APC-specific modifications. Missense variants: when the variant under assessment results in the same amino acid change as previously established Pathogenic variant(s). (Moderate strength: same, keyed to a previously established Likely Pathogenic variant.)

Evidence considered

• ClinGen InSiGHT APC VCEP specification v2.1 (cspec), PS1 Strong rule: 'The previously established variant was classified as Pathogenic according to the APC-specific modifications. This criterion can be applied to both missense and splice variants in APC. Missense variants: when the variant under assessment results in the same amino acid change as previously established Pathogenic variant(s). There are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other variants leading to the same missense change at these positions meet PS1_Moderate. No missense variant has been classified as Pathogenic based on current evidence.'
• ClinGen InSiGHT APC VCEP specification v2.1 (cspec), PS1 Moderate rule: same amino-acid-change logic but keyed to a previously established Likely Pathogenic variant; the only named Likely Pathogenic APC missense variants are p.(Asn1026Ser) and p.(Ser1028Arg).
• APC VCEP supplementary material (vcep_apc_specifications_supplementary_material_v2) notes for PS1: 'Based on the current knowledge there are only two ...' Likely Pathogenic missense variants, consistent with the rule text.
• The variant under assessment is p.(Thr1082Ser) (residue 1082), which is neither residue 1026 nor residue 1028 and matches none of the named established (Likely) Pathogenic missense changes.
• ClinVar (clinvar) variation 181799: NM_000038.6(APC):c.3245C>G (p.Thr1082Ser) is reported as conflicting - uncertain significance in 9 clinical laboratories and likely benign in 5 clinical laboratories; review status 'criteria provided, conflicting classifications'; 0 expert-panel submissions; date last updated 2026-06-20. The variant itself is therefore not an established Pathogenic or Likely Pathogenic variant.
• Kraus et al. 2015 (PMID:25142776): the p.Thr1082Ser variant was reported once (52-year-old male colorectal cancer patient, patient 72) and classified with the IARC five-class system as class 2 ('likely not pathogenic'), with PolyPhen-2 'B' (benign), SIFT 'T' (tolerated), Align-GVGD score 2, and absent from the NHLBI ESP control dataset.

Still missing

• No full text or structured extract was available for PMID:25559809 (Chubb et al. 2015), which is cited by several ClinVar submitters for this variant; if it established p.Thr1082Ser as (Likely) Pathogenic it could bear on PS1, but its ClinVar submissions are uncertain significance/likely benign and the APC VCEP states no APC missense variant is classified Pathogenic.

Sources

Reasoning

Governing specification is the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP for APC v2.1, which redefines PS4 from a case-control odds-ratio criterion into a phenotype-points criterion: >=16 points Pathogenic Very Strong, 4-15.5 Strong, 2-3.5 Moderate, 1-1.5 Supporting, with points assigned per Table 1 and the supplementary-material modification based on Fortuno et al. 2020. No affected-cohort enrichment statistic (odds ratio / relative risk) exists for APC c.3245C>G (p.Thr1082Ser). The only reported carrier is a single unselected 52-year-old male colorectal-cancer case (PMID:25142776, patient 72, Table 4), microsatellite-stable tumour, with no adenoma count or colorectal polyposis phenotype reported; under Table 1 a colorectal-cancer diagnosis without a documented polyposis phenotype (or desmoid/medulloblastoma/hepatoblastoma/CHRPE/gastric-duodenal adenoma/osteoma/family-history feature) scores 0 phenotype points, and that same report itself assigned the variant IARC class 2 ('likely not pathogenic'). Comparison as literally written for PS4 (operator '>='; PS4 strengthens as points increase): assigned phenotype points 0 >= 1 (PS4_Supporting threshold)? No. PS4 is therefore not met at any strength.

Rule

APC VCEP v2.1 PS4 (phenotype points): >=16 points = Pathogenic Very Strong; 4-15.5 = Strong; 2-3.5 = Moderate; 1-1.5 = Supporting (points curated per Table 1).

Evidence considered

• APC VCEP v2.1 (ClinGen InSiGHT) PS4 rules: >=16 phenotype points Very Strong; 4-15.5 Strong; 2-3.5 Moderate; 1-1.5 Supporting; phenotype points curated per Table 1 (modification based on Fortuno et al. 2020).
• Table 1 (Phenotypic consistency / phenotype point per proband): typical colorectal phenotype 20-99 adenomas = 1 point; other colorectal phenotype >=20 adenomas, multifocal/bilateral CHRPE, >=2 gastric adenomas, >=2 duodenal adenomas, osteomas, or typical FAP family history = 0.5 point. A colorectal cancer without any of these features scores 0 points.
• The single exact-variant carrier reported in the literature (PMID:25142776, Table 4, patient 72) is an unselected 52-year-old male colorectal-cancer case with an MSS tumour and normal MMR IHC; no polyposis/adenoma-count phenotype is recorded, so 0 phenotype points are assignable.
• No case-control or case-enrichment data (odds ratio / relative risk) for APC c.3245C>G was present in the assembled evidence.
• Explicit comparison for PS4 (operator '>=' exactly as written in the APC VCEP PS4 rule, and higher points = stronger): assigned phenotype points 0 >= 1 (PS4_Supporting)? no -> not met.

Still missing

• No proband phenotype (adenoma count, polyposis features, or other Table 1 features) is documented for this variant, so PS4 phenotype points were assigned as 0 by default rather than by active curation.
• No case-control enrichment study (odds ratio / relative risk with confidence interval excluding 1.0) specific to this variant was identified.

Sources

Reasoning

Governing framework is the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP specification for APC v2.1 (not generic ACMG). Its PM2_supporting rule defines 'rare in controls' as an allele frequency <= 0.0003% (0.000003) when the allele count is > 1, or an allele frequency < 0.001% (0.00001) when the allele count is <= 1, and instructionsToUse direct use of the total population from the gnomAD v2.1.1 non-cancer dataset. In the non-cancer gnomAD v2.1 subset the allele count is 11 (> 1), so the applicable threshold is 0.000003. The observed non-cancer exome allele frequency is 4.6605e-05 (0.00466%), roughly 15-fold above the threshold; the non-cancer total AF is 4.861e-05. The variant is likewise too frequent in the all-comers datasets (v2.1 total AF 4.614e-05 with AC 13; v4.1 total AF 6.877e-05 with AC 111), all with allele counts > 1. Because the allele frequency exceeds 0.000003 with an allele count > 1, the rarity condition is not satisfied and PM2 is not met.

Rule

Rare in controls: allele frequency <= 0.0003% (0.000003) if the allele count is > 1, OR allele frequency < 0.001% (0.00001) if the allele count is <= 1. [InSiGHT APC VCEP v2.1, Pathogenic Supporting; use the total population from the gnomAD v2.1.1 non-cancer dataset]

Evidence considered

• Governing specification: InSiGHT APC VCEP v2.1. PM2 supporting rule: 'Rare in controls, defined by an allele frequency <= 0.0003% (0.000003) if the allele count is > 1 OR by an allele frequency < 0.001% (0.00001) if the allele count is <= 1.' instructionsToUse: 'General recommendation: Use the total population from the non-cancer dataset from gnomAD (v2.1.1)'.
• gnomAD v2.1.1 non-cancer subset (exomes-only figures): AC 11, AN 236026, exome AF 4.6605035e-05 (0.00466%); total across non-cancer 13/267434 = 4.861e-05. Allele count is > 1, so the applicable rarity threshold is 0.000003, which is exceeded.
• gnomAD v2.1 all-comers: AC 13, AN 281722, total AF 4.6144781e-05 (0.00461%). gnomAD v4.1 all-comers: AC 111, AN 1614042, total AF 6.877144e-05 (0.00688%). Both also exceed the 0.000003 threshold with allele count > 1.
• gnomAD v3.1 non-cancer (genomes only): AC 7, AN 147964, AF 4.73088e-05 (0.00473%) - also above threshold with allele count > 1.
• The variant is present at 11-111 alleles in control populations with zero homozygotes, i.e. it is not rare enough to qualify for PM2_supporting under the VCEP rule.

Sources

Reasoning

Variant consequence: missense, NP_001120982.1:p.(Thr1082Ser) (NM_001127510.3:c.3245C>G), APC. The governing ClinGen InSiGHT APC VCEP specification v2.1 makes PM5 applicable but defines it narrowly: PM5 is met (Moderate, or Supporting) only when a different missense variant at the same amino acid residue has been determined to be Pathogenic (or Likely Pathogenic) under the APC-specific modifications. The specification explicitly states that APC currently has only two Likely Pathogenic missense variants, c.3077A>G p.(Asn1026Ser) (residue 1026) and c.3084T>A p.(Ser1028Arg) (residue 1028), and that other different missense variants at these positions meet PM5_supporting; no missense variant has been classified as Pathogenic. It further requires that the Grantham distance of the variant under assessment be equal to or higher than that of the reported comparator. The variant under assessment alters residue 1082, which is neither residue 1026 nor residue 1028, so the same-residue comparator condition cannot be satisfied and the Grantham-distance test is moot. The pm5_candidates.json harvest independently found 0 same-residue candidates among the 15 records seen, 0 expert-panel Pathogenic/Likely Pathogenic candidates, and 0 non-expert-majority P/LP candidates at residue 1082; although that harvest recorded an HTTP 429 error, the governing rule excludes residue 1082 regardless of any ClinVar record. ClinVar contains no Pathogenic or Likely Pathogenic alternate missense at APC residue 1082. PM5 is therefore not met.

Rule

APC VCEP v2.1 PM5 (Moderate/Supporting): The reported missense variant was determined to be (Likely) Pathogenic according to the APC-specific modifications; other different missense variants at these positions (p.Asn1026Ser, p.Ser1028Arg) meet PM5_supporting, and the Grantham distance of the assessed variant must be equal or higher than the reported variant.

Evidence considered

• ClinGen InSiGHT APC VCEP specification v2.1 (cspec), PM5 Moderate rule: 'The reported missense variant was determined to be Pathogenic according to the APC-specific modifications. There are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other different missense variants at these positions meet PM5_supporting. No missense variant has been classified as Pathogenic based on current evidence. Grantham's distance of the variant under assessment must have an equal or higher score than the reported variant.' The Supporting tier is the same logic keyed to a previously established Likely Pathogenic variant.
• APC VCEP supplementary material (vcep_apc_specifications_supplementary_material_v2), PM5 row: 'Do not use if the mechanism of pathogenicity for t...' (VCEP comment table entry for PM5).
• The variant under assessment alters residue 1082 (p.Thr1082Ser), which is neither the established Likely Pathogenic residue 1026 (p.Asn1026Ser) nor residue 1028 (p.Ser1028Arg), so no same-residue comparator exists and the Grantham-distance requirement cannot be invoked.
• pm5_candidates.json (pm5_candidates): mode 'classic_same_residue_missense'; total_candidates_seen 15, same_residue_candidates 0, expert_panel_plp_candidates 0, non_expert_majority_plp_candidates 0; recommendation level 'no_useful_candidates_found'; the run also recorded an 'HTTP Error 429: Too Many Requests'.
• ClinVar (clinvar) variation 181799 for NM_000038.6(APC):c.3245C>G (p.Thr1082Ser): conflicting classifications (9 uncertain significance, 5 likely benign), 0 expert-panel submissions; no alternate missense at APC residue 1082 is reported as Pathogenic or Likely Pathogenic.
• Kraus et al. 2015 (PMID:25142776) reported p.Thr1082Ser once as IARC class 2 ('likely not pathogenic'), providing no pathogenic comparator at residue 1082.

Still missing

• The ClinVar same-residue harvest in pm5_candidates.json hit an HTTP 429 (rate-limit) error, so its candidate list may be incomplete; this does not change the conclusion because the APC VCEP restricts PM5 to the two established Likely Pathogenic residues (1026 and 1028), which exclude residue 1082.

Sources

Reasoning

Variant consequence: missense, NP_001120982.1:p.(Thr1082Ser) (NM_001127510.3:c.3245C>G), APC. The governing framework is the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel specification for APC v2.1 (cspec), which is applicable and takes precedence over generic ACMG. The APC VCEP PP3 rule for missense variants states: 'Do not use computational prediction models for conservation, evolution, etc. In silico splicing predictors should be used for presumed missense variants to reveal possible splicing effects.' Accordingly, for this missense variant PP3 is evaluated on the splice-prediction path (SpliceAI and other VCEP-recommended tools), not on the missense protein-impact path. SpliceAI Lookup for NM_001127510.3:c.3245C>G returns DS_AG 0.001, DS_AL 0.0, DS_DG 0.0, DS_DL 0.0 (max delta score 0.001), i.e. no predicted splice impact; this is far below the generic SpliceAI PP3 supporting cutoff of >= 0.2 (Jaganathan et al. 2019, PMID:30661751), and no VCEP-specific SpliceAI threshold supersedes it. PP3 therefore is not met. For completeness on the non-designated path, REVEL = 0.293 is also below the generic PP3 supporting cutoff of >= 0.644 (Pejaver et al. 2022, PMID:36413997), so the conclusion is unchanged under either reckoning. BayesDel = -0.278933 has no established generic ACMG-strength calibration and is therefore not used. No splice prediction from the VCEP-recommended MaxEntScan or VarSeak tools was retrieved, so multi-tool concordance was not established; however, a single VCEP-recommended tool (SpliceAI) at 0.001 does not support a deleterious splice effect, and the VCEP rule requires multiple splicing predictors to support a deleterious effect, so PP3 is not met.

Rule

APC VCEP v2.1 PP3 (Supporting): Missense variants: Do not use computational prediction models for conservation, evolution, etc. In silico splicing predictors should be used for presumed missense variants to reveal possible splicing effects. Non-canonical splicing variants: Multiple in silico splicing predictors support a deleterious effect.

Evidence considered

• ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specification for APC v2.1 (cspec), PP3 supporting rule: 'Missense variants: Do not use computational prediction models for conservation, evolution, etc. In silico splicing predictors should be used for presumed missense variants to reveal possible splicing effects. Non-canonical splicing variants: Multiple in silico splicing predictors support a deleterious effect.'
• APC VCEP v2.1 PP3 'instructionsToUse': 'Recommended splice prediction programs: see PS1', which lists SpliceAI, MaxEntScan, and VarSeak.
• SpliceAI Lookup (spliceai) for NM_001127510.3:c.3245C>G / 5-112174536-C-G: DS_AG 0.001, DS_AL 0.0, DS_DG 0.0, DS_DL 0.0; max delta score 0.001 (reported as 'no significant splice impact').
• Generic SpliceAI calibration used as data: PP3 supporting requires max delta >= 0.2 and moderate requires >= 0.5 (Jaganathan et al. 2019, Cell; PMID:30661751); observed max delta 0.001 is below both.
• REVEL score 0.293 (local REVEL v1.3 lookup) is below the generic PP3 supporting cutoff of >= 0.644; REVEL is additionally not the APC VCEP's designated missense PP3 path, which directs splicing predictors instead.
• BayesDel score -0.278933 (local BayesDel lookup): no generic ACMG-strength PP3/BP4 calibration is established, so BayesDel is not used for this criterion.
• Variant is not at a canonical splice consensus site (PVS1 assessment: canonical_splice_consensus false), and the SpliceAI result provides no evidence of a splice-region effect.

Still missing

• MaxEntScan and VarSeak (the other VCEP-recommended splice prediction programs) were not retrieved, so multi-tool concordance for the missense splice path could not be established; SpliceAI alone at max delta 0.001 does not support a deleterious splice effect.

Sources

Reasoning

Governing framework is the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP specification for APC v2.1 (not generic ACMG). Its BA1 stand-alone rule requires a gnomAD Popmax Filtering Allele Frequency (AF) >= 0.1% (0.001), and the specification's instructionsToUse direct that this be assessed in the gnomAD v2.1.1 non-cancer dataset. In the non-cancer gnomAD v2.1 subset this variant has an exome allele frequency of 4.6605e-05 (11/236026 alleles, 0 homozygotes) and a non-cancer grpmax filtering AF of 3.865e-05 (0.003865%); the highest single population is European (Finnish) at 0.000119512 (0.01195%). For completeness the all-comers gnomAD v2.1 grpmax filtering AF is 3.442e-05 (0.003442%) and gnomAD v4.1 gives a total AF of 6.877e-05 with a grpmax filtering AF of 7.076e-05 (0.007076%). Every observed filtering frequency is roughly 10- to 25-fold below the 0.1% stand-alone threshold, and no population approaches it, so BA1 is not met.

Rule

GnomAD Popmax Filtering Allele Frequency (AF) >= 0.1% (0.001). [InSiGHT APC VCEP v2.1, Benign Stand Alone; assess in the gnomAD v2.1.1 non-cancer dataset]

Evidence considered

• Governing specification: ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP for APC v2.1 (doc id 1529292791). BA1 strength rule: 'GnomAD Popmax Filtering Allele Frequency (AF) >= 0.1% (0.001).' instructionsToUse: 'General recommendation: Use the non-cancer dataset from gnomAD (v2.1.1)'.
• gnomAD v2.1.1 non-cancer subset (exomes-only figures): total/exome AC 11, AN 236026, exome AF 4.6605035e-05, homozygotes 0; non-cancer grpmax filtering AF 3.865e-05; highest subpopulation European (Finnish) AF 0.00011951238945103975 (3/25102), homozygotes 0.
• gnomAD v2.1 all-comers: total AC 13, AN 281722, total AF 4.6144781e-05, homozygotes 0; grpmax filtering AF 3.442e-05; highest subpopulation European (Finnish) AF 0.0001194362608487937 (3/25118).
• gnomAD v4.1 all-comers: total AC 111, AN 1614042, total AF 6.877144e-05, homozygotes 0; grpmax filtering AF 7.076e-05; highest subpopulation 'Remaining individuals' AF 0.00011202867934191153 (7/62484).
• All observed popmax/grpmax filtering frequencies (3.442e-05 to 7.076e-05) are far below the VCEP BA1 threshold of 1e-03.

Sources

Reasoning

Governing framework is the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP specification for APC v2.1. Its BS2 strong rule is '>=10 points for healthy individuals OR >=2 times in homozygous state' and the supporting rule is '>=3 points for healthy individuals'. The homozygous arm fails outright: homozygote counts are 0 in every gnomAD dataset examined (v2.1 all-comers 0; v2.1 non-cancer exomes 0; v3.1 non-cancer 0; v4.1 all-comers 0), so the '>=2 times in homozygous state' condition is not satisfied. The healthy-individual arm also fails: the VCEP instructionsToUse explicitly states that the gnomAD v2.1.1 non-cancer dataset cannot be used to count heterozygous healthy individuals, only to search for homozygous individuals, so the 11 non-cancer exome carriers cannot be scored as 0.5-point healthy individuals, and the remaining accessible literature contains no report of this variant in a healthy or unaffected adult (the only cohort observation, PMID:25142776, is an affected 52-year-old male colorectal cancer patient). No healthy-individual points can therefore be accumulated. BS2 is not met.

Rule

>= 10 points for healthy individuals OR >= 2 times in homozygous state (Strong); >= 3 points for healthy individuals (Supporting). [InSiGHT APC VCEP v2.1; gnomAD v2.1.1 non-cancer dataset may only be searched for homozygous individuals, not heterozygous healthy individuals]

Evidence considered

• Governing specification: InSiGHT APC VCEP v2.1. BS2 strong rule: '>= 10 points for healthy individuals OR >= 2 times in homozygous state.' BS2 supporting rule: '>= 3 points for healthy individuals.' A healthy individual is worth 1 point if age >=50 plus <5 adenomatous polyps and absence of Table 1 features, or age >=50 with colorectal cancer/polyposis not the testing indication; 0.5 points for keywords control, non-cancer, normal, unaffected population.
• BS2 instructionsToUse: 'The non-cancer dataset from gnomAD (v2.1.1) cannot be used for "heterozygous healthy individuals", because of the limited phenotype information and since it is usually already used for BA1/BS1. However, the non-cancer dataset from gnomAD (v2.1.1) can be used to search for homozygous individuals.'
• Homozygote counts are 0 in all gnomAD datasets: v2.1 all-comers total_hom 0; v2.1 non-cancer exome_hom 0 and total_hom 0; v3.1 non-cancer genome_hom 0; v4.1 all-comers total_hom 0. The '>=2 times in homozygous state' arm therefore fails.
• PMID:25142776 (Table 4, patient 72) reports the variant once in a 52-year-old male colorectal cancer patient classified by the IARC five-class system as class 2 ('likely not pathogenic'); this is an affected individual, not a healthy individual, and contributes no BS2 points.
• PMID:25645574, PMID:25452455, PMID:25741868 and PMID:28492532 were reviewed and contain no variant-specific or control-cohort data on this variant.

Still missing

• PMID:25559809 is cited by five ClinVar submissions for this variant but was captured as a page image only (no extracted full text), so it could not be screened for reports of the variant in healthy or unaffected (control) individuals; this is the one source that could add healthy-individual points for BS2 and is flagged for human review.
• No case-level phenotyping (age >=50 plus colonoscopy findings) is available for any carrier in this case; gnomAD does not expose the phenotype detail required to score 1-point healthy individuals.

Sources

Reasoning

The APC VCEP specification (Version 2.1) makes BP2 applicable with the rule: 'Observed in trans with a (Likely) Pathogenic APC variant OR >= 3 times in an unknown phase with different (Likely) Pathogenic APC variants.' Both arms require documented co-occurrence with a (likely) pathogenic APC allele, either with confirmed trans phase or at least three independent unknown-phase observations with different pathogenic APC variants. No source in this case reports c.3245C>G in trans with any pathogenic or likely pathogenic APC variant, and no phasing information (cis/trans) exists for this variant. The only variant-specific report (PMID:25142776) lists c.3245C>G once, in a single 52-year-old male colorectal cancer patient (patient 72, Table 4), classified as IARC class 2 ('likely not pathogenic'), with no second germline APC variant described; the somatic APC second-hit changes discussed in that paper are p.Arg414Cys and p.Ser2621Cys, unrelated to this locus. ClinVar (VCV000181799) shows no expert-panel submission and reports conflicting interpretations (9 laboratories Uncertain significance, 5 Likely benign, 0 expert panels), and none of the submissions report a cis/trans relationship. The unknown-phase arm is likewise unmet: there are zero observations of this variant co-occurring with different (likely) pathogenic APC variants, against the required >= 3. BP2 is therefore not met.

Rule

Observed in trans with a (Likely) Pathogenic APC variant OR >= 3 times in an unknown phase with different (Likely) Pathogenic APC variants (APC VCEP v2.1, Benign Supporting).

Evidence considered

• APC VCEP BP2 rule (Version 2.1): the variant must be observed in trans with a (Likely) Pathogenic APC variant, OR at least 3 times in an unknown phase with different (Likely) Pathogenic APC variants.
• ClinVar (VCV000181799, ClinVarID 181799) provides no expert-panel submission and no phase information; 14 submitters report conflicting classifications (9 Uncertain significance, 5 Likely benign), none reporting a cis/trans relationship with another APC variant.
• PMID:25142776 reports c.3245C>G (p.Thr1082Ser) once, in a 52-year-old male colorectal cancer patient (patient 72, Table 4), IARC class 2 ('likely not pathogenic'); no second germline APC variant and no phasing are documented, and the somatic second-hit APC findings in that paper concern p.Arg414Cys and p.Ser2621Cys, not this locus.
• No collection source (ClinVar submissions, literature pass, or fetched full texts) contains an observation of this variant co-occurring in trans or repeatedly in unknown phase with a (likely) pathogenic APC variant.

Still missing

• No phased genotype data (cis/trans) is available for this variant in any source; the assessment rests on the absence of any reported in-trans or repeated unknown-phase co-occurrence with a (likely) pathogenic APC variant.
• PMID:25559809 (Chubb et al., familial CRC exome sequencing) was cited by ClinVar submissions but no full text was fetched, so any family/phase data it might contain was not independently verified.

Sources

Reasoning

Governing specification is the APC VCEP v2.1 (ClinGen InSiGHT), which applies BP5_Supporting only when a (Likely) Pathogenic variant in another adenomatous polyposis gene is present, namely heterozygous variants in POLD1 or POLE; biallelic variants in MUTYH, NTHL1 or MSH3; or, in patients with onset in childhood/adolescence, biallelic variants in MLH1, MSH2, MSH6 or PMS2, and only when a colorectal polyposis phenotype is present. In this case only APC c.3245C>G (p.Thr1082Ser) was assessed. No variant in any other adenomatous polyposis gene is reported, no biallelic MUTYH/NTHL1/MSH3 or MMR result is present, and no colorectal polyposis phenotype is documented, so there is no alternate molecular basis for the polyposis phenotype to invoke. Explicit comparison on this criterion's own evidence (a non-numeric presence/absence condition): alternate-basis variant present? No. BP5 is therefore not met.

Rule

APC VCEP v2.1 BP5_Supporting: a (Likely) Pathogenic variant in another adenomatous polyposis gene (heterozygous POLD1/POLE; biallelic MUTYH, NTHL1 or MSH3; childhood/adolescence-onset biallelic MLH1/MSH2/MSH6/PMS2) in a patient with a colorectal polyposis phenotype.

Evidence considered

• APC VCEP v2.1 (ClinGen InSiGHT) BP5_Supporting: applicable only for an alternate genetic basis of the colorectal polyposis phenotype.
• InSiGHT supplementary instructions define the qualifying alternate basis as a (Likely) Pathogenic variant in another adenomatous polyposis gene: heterozygous POLD1 or POLE; biallelic MUTYH, NTHL1 or MSH3; or, with childhood/adolescence onset, biallelic MLH1/MSH2/MSH6/PMS2; and note the rule is only applicable when a colorectal polyposis phenotype is present.
• Case evidence contains only the APC variant under assessment; no other gene result and no colorectal polyposis phenotype are documented, so the alternate-basis condition is absent.

Still missing

• No multi-gene adenomatous-polyposis panel result (MUTYH, NTHL1, MSH3, POLD1, POLE, and MMR genes) or documented colorectal polyposis phenotype is available for this case, so an alternate genetic basis cannot be excluded or confirmed.

Sources

Reasoning

Governing framework is the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specification for APC v2.1, where PS2 is graded on a curated per-proband de novo score: Very Strong at >=4 de novo scores, Strong at 2-3.5, Moderate at 1-1.5. The de novo score itself is built from the VCEP Table 1/2 rule that a proband with >=1 phenotype point and confirmed maternity and paternity contributes 2 points (1 point if phenotype is only 0.5). This case contains no proband, no parental/paternity-maternity testing, and no family information of any kind; the review is variant-level only. The only variant-level case observation, PMID:25142776, reports c.3245C>G (p.Thr1082Ser) in a single 52-year-old male colorectal cancer patient with no parental testing, no statement of de novo origin, and no relatives studied. No de novo score can therefore be computed, so PS2 cannot be evaluated and is recorded as not assessed rather than not met.

Rule

APC VCEP v2.1 PS2: >=4 de novo scores = Very Strong; 2-3.5 de novo scores = Strong; 1-1.5 de novo scores = Moderate. Per-proband de novo score: 2 for >=1 phenotype point with confirmed parental relationships (1 if unconfirmed); 1 for 0.5 phenotype points with confirmed parental relationships (0.5 if unconfirmed).

Evidence considered

• Governing framework: ClinGen InSiGHT APC VCEP v2.1 defines PS2 on a curated de novo score, Very Strong at >=4 de novo scores, Strong at 2-3.5, Moderate at 1-1.5; the per-proband de novo score is 2 when the proband has >=1 phenotype point and confirmed parental relationships, or 1 when the proband has 0.5 phenotype points with confirmed parental relationships (VCEP Tables 1 and 2).
• The case was searched for a proband with a documented de novo occurrence and confirmed maternity/paternity. No proband, no parental testing, and no family/pedigree data exist in any case file; the assessment is variant-level (ClinVar records plus literature).
• PMID:25142776, the only source that reports this specific variant, describes one 52-year-old male colorectal cancer patient carrying c.3245C>G (p.Thr1082Ser); the paper reports no parental testing, no de novo origin, and no relatives, so no de novo score is computable.
• No criterion was inferred from any source's final classification; ClinVar submissions for this variant provide classifications only and no de novo/parental data.

Still missing

• No proband with confirmed maternity/paternity and a documented de novo occurrence of c.3245C>G is available.
• No phenotype-point curation (VCEP Table 1) for any carrier proband is available, so the de novo score cannot be derived even in principle.

Sources

Reasoning

The governing specification is the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel APC specification v2.1 (source key 'cspec'), which supplants generic ACMG/AMP for this gene. Under that specification PS3 requires functional assay evidence: RNA assays demonstrating a premature stop codon or inframe skipping of exon 13 or 14 with reduced/absent full-length transcript (Very Strong/Strong/Moderate tiers), or, at Supporting strength, a protein assay showing increased beta-catenin-regulated transcription activity and/or decreased beta-catenin binding by surface plasmon resonance for variants within the beta-catenin binding domain (codons 959-2129). The variant under assessment is a missense change, NM_001127510.3:c.3245C>G p.(Thr1082Ser), at codon 1082, which lies within the codons 959-2129 beta-catenin binding domain, so the protein-assay branch is applicable in principle and the RNA branch is not (RNA-assay tiers are designed for splice/coding-aberration readouts). No functional evidence of any kind is available for this variant: none of the triaged/fetched full texts (PMID:25142776, PMID:25452455, PMID:25645574, PMID:25741868, PMID:28492532) reports an RNA or protein functional assay for c.3245C>G, the ClinVar record for this variant contains no expert-panel assertion and no functional-assay submission data, and OncoKB explicitly reports no variant-specific reviewed functional evidence. Because the required assay evidence has not been generated or reported, PS3 can neither be met nor refuted and is recorded as not_assessed rather than not_met; the outcome is unchanged either way as neither state adds pathogenic evidence.

Rule

APC VCEP v2.1 PS3 (RNA assay tiers Very Strong/Strong/Moderate; protein-assay branch Supporting, restricted to codons 959-2129)

Evidence considered

• APC VCEP v2.1 PS3 rule (source key 'cspec'): Very Strong = RNA assays show a premature stop codon OR inframe skipping of exon 13 or 14 AND absence of full-length transcript; Strong = same aberrations AND <10% of full-length transcript; Moderate = premature stop codon or inframe exon 13/14 skipping together with reports of exon deletion/skipping/loss or intronic insertion, or other inframe skipping with absent or <10% full-length transcript; Supporting = other inframe skipping with those reports, or over-expression of an alternative transcript (exons 10, 11 or 15), or protein assays showing increased beta-catenin-regulated transcription activity and/or decreased beta-catenin binding by surface plasmon resonance, restricted to variants within the beta-catenin binding domain (codons 959-2129 of APC).
• Variant consequence: NM_001127510.3:c.3245C>G encodes NP_001120982.1:p.(Thr1082Ser), a missense substitution at codon 1082, i.e. inside the codons 959-2129 beta-catenin binding domain cited by the APC VCEP for the protein-assay branch.
• No functional assay data located: the only fetched full text that mentions the variant (PMID:25142776) reports it from an 18-gene NGS germline screen of 152 colorectal cancer patients and characterises it only by in silico tools (PolyPhen-2 benign, SIFT tolerated, Align-GVGD 2) and ESP frequency 0%; it performs no RNA or protein functional assay.
• PMID:25741868 (ACMG/AMP 2015) defines PS3/BS3 generically as well-established in vitro/in vivo functional studies; it provides no variant-specific assay data and its generic text is superseded here by the APC VCEP specification.
• PMID:28492532 (Sherloc) discusses weighting of functional versus clinical evidence generally and reports no APC-specific or variant-specific assay; APC is not mentioned in the paper.
• OncoKB query for APC T1082S returned 'Unknown Oncogenic Effect' with no citations and an explicit statement that no variant-specific reviewed functional evidence was identified.
• ClinVar (variation 181799): no expert-panel submission; classifications are Uncertain significance (9 laboratories) and Likely benign (5 laboratories); the validated citation trail (PMID:25142776, 25559809, 34250417, 28873162) does not include a functional-assay publication.

Still missing

• No RNA assay (premature stop codon / inframe exon 13 or 14 skipping with quantification of full-length transcript) has been reported for APC c.3245C>G.
• No protein assay (beta-catenin-regulated transcription activity or surface plasmon resonance binding) has been reported for this variant, despite p.Thr1082Ser lying within the codons 959-2129 beta-catenin binding domain where the APC VCEP makes the protein-assay PS3 branch applicable.
• No candidate functional-study publication was captured in the literature triage for this variant; a targeted search of the primary functional-assay literature for APC beta-catenin-domain missense variants would be required to close this gap.

Sources

Reasoning

Under the governing ClinGen InSiGHT APC VCEP v2.1 specification, PM6 is graded on the same curated de novo score as PS2 but covers assumed de novo with unconfirmed parental relationships: 2-3.5 de novo scores is Strong, 1-1.5 is Moderate, and 0.5 is Supporting, where a proband with >=1 phenotype point and unconfirmed parental relationships yields 1 de novo score and a proband with 0.5 phenotype points yields 0.5 (VCEP Tables 1 and 2). This case documents no proband and no de novo occurrence at all, confirmed or assumed, and no parental testing exists that could even support an assumption of de novo. The single variant-level case report (PMID:25142776) again describes only one adult colorectal cancer patient with no family testing. With neither a de novo observation nor phenotype-point data, no de novo score can be assigned, so PM6 cannot be evaluated and is recorded as not assessed.

Rule

APC VCEP v2.1 PM6: 2-3.5 de novo scores = Strong; 1-1.5 de novo scores = Moderate; 0.5 de novo score = Supporting (assumed de novo, parental relationships unconfirmed; score per proband 1 for >=1 phenotype point, 0.5 for 0.5 phenotype points).

Evidence considered

• Governing framework: ClinGen InSiGHT APC VCEP v2.1 defines PM6 on the curated de novo score with unconfirmed parental relationships, Strong at 2-3.5 de novo scores, Moderate at 1-1.5, Supporting at 0.5; the per-proband score is 1 for >=1 phenotype point and 0.5 for 0.5 phenotype points when parental relationships are unconfirmed (VCEP Tables 1 and 2).
• The case was searched for any statement that this variant arose de novo, including unconfirmed/assumed de novo. None exists: there is no proband, no parental testing, and no family information in the ClinVar records, case summary, or evidence bundle.
• PMID:25142776 reports the variant in a single 52-year-old male colorectal cancer patient with no relatives tested and no de novo statement, providing no basis for an assumed-de-novo score.

Still missing

• No de novo occurrence (confirmed or assumed) of c.3245C>G is reported in any source.
• No parental testing or proband phenotype-point curation is available to derive an assumed-de-novo score.

Sources

Reasoning

The governing ClinGen InSiGHT APC VCEP v2.1 specification grades PP1 by counted meioses: Strong when the variant segregates in >=7 meioses in >=2 families, Moderate in 5-6 meioses in >=1 family, and Supporting in 3-4 meioses in >=1 family. Evaluating PP1 therefore requires a family pedigree with genotyped affected and unaffected relatives, i.e. a countable number of informative meioses. This case provides none: it is a variant-level assessment with no proband, no pedigree, and no relatives genotyped. The only source reporting the variant, PMID:25142776, describes a single 52-year-old male colorectal cancer patient and explicitly reports no segregation; the ClinVar submissions for this variant carry classifications only and no family or cosegregation data. With zero countable meioses, PP1 cannot be evaluated and is recorded as not assessed rather than not met.

Rule

APC VCEP v2.1 PP1: variant segregates in >=7 meioses in >=2 families = Strong; 5-6 meioses in >=1 family = Moderate; 3-4 meioses in >=1 family = Supporting.

Evidence considered

• Governing framework: ClinGen InSiGHT APC VCEP v2.1 grades PP1 as Strong for segregation in >=7 meioses in >=2 families, Moderate for 5-6 meioses in >=1 family, and Supporting for 3-4 meioses in >=1 family; the supplementary material records that the APC PP1 modification follows Luo et al. 2019.
• The case was searched for a pedigree, meiosis counts, or any co-segregation statement. No proband, pedigree, or genotyped relatives exist in the case files; the review is variant-level.
• PMID:25142776 reports c.3245C>G (p.Thr1082Ser) in one 52-year-old male colorectal cancer patient and provides no segregation data and no genotyped relatives.
• ClinVar records for this variant (9 laboratories reporting Uncertain significance, 5 reporting Likely benign) supply classifications only; no submission reports family cosegregation, and criterion status is never inferred from another source's final classification.

Still missing

• No family pedigree or meiosis count is available for c.3245C>G.
• No co-segregation with disease has been reported in any source, and no relatives of the single reported carrier were genotyped.

Sources

Reasoning

The governing specification is the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel APC specification v2.1 (source key 'cspec'). Under that specification BS3 is met at Strong strength by an RNA assay of a synonymous or intronic variant in a constitutional patient sample showing no mRNA aberration AND demonstration of biallelic expression and/or use of nonsense-mediated decay inhibition, or at Supporting strength by such an RNA assay without those confirmations, OR by a protein assay showing retention of beta-catenin-regulated transcription activity comparable to wild-type for variants within the beta-catenin binding domain (codons 959-2129). The variant is a missense change, NM_001127510.3:c.3245C>G p.(Thr1082Ser); the RNA-assay branches are defined for synonymous or intronic variants and therefore do not apply to it, while the protein-assay branch does apply because codon 1082 lies within codons 959-2129. No functional assay of either type has been reported for this variant: none of the fetched full texts reports an RNA or protein assay for c.3245C>G, the ClinVar record carries no expert-panel assertion or assay data, and OncoKB reports no variant-specific reviewed functional evidence. With no retention-of-function assay available, BS3 can neither be met nor refuted and is recorded as not_assessed rather than not_met; the outcome is unchanged either way as neither state adds benign evidence.

Rule

APC VCEP v2.1 BS3 (RNA-assay branches defined for synonymous/intronic variants; protein-assay branch Supporting, restricted to codons 959-2129)

Evidence considered

• APC VCEP v2.1 BS3 rule (source key 'cspec'): Strong = RNA assay of a synonymous or intronic variant in a constitutional patient sample demonstrates no mRNA aberration AND biallelic expression is shown and/or nonsense-mediated decay inhibition was used; Supporting = such an RNA assay without those confirmations, OR a protein assay showing retention of beta-catenin regulated transcription activity comparable to wild-type, restricted to variants within the beta-catenin binding domain (codons 959-2129 of APC).
• Variant consequence: NM_001127510.3:c.3245C>G encodes NP_001120982.1:p.(Thr1082Ser), a missense substitution; the RNA-assay BS3 branches (synonymous or intronic variant) are inapplicable, leaving only the protein-assay branch, which applies because codon 1082 is within codons 959-2129.
• No functional assay data located for this variant: the only fetched full text mentioning it (PMID:25142776) reports it from a germline NGS screen with in silico characterisation only (PolyPhen-2 benign, SIFT tolerated, Align-GVGD 2) and performs no RNA or protein functional assay.
• PMID:25741868 (ACMG/AMP 2015) defines BS3 generically as well-established functional studies showing no damaging effect; it supplies no variant-specific assay data and its generic text is superseded here by the APC VCEP specification.
• PMID:28492532 (Sherloc) reports no APC-specific or variant-specific assay and does not mention APC; it contributes no variant-level functional evidence.
• OncoKB query for APC T1082S returned 'Unknown Oncogenic Effect' with no citations and an explicit statement that no variant-specific reviewed functional evidence was identified.
• ClinVar (variation 181799): no expert-panel submission and no functional-assay evidence in the submission trail; classifications are Uncertain significance (9 laboratories) and Likely benign (5 laboratories), the latter not accompanied by a published functional-assay basis.

Still missing

• No protein assay measuring beta-catenin-regulated transcription activity (retention comparable to wild-type) has been reported for APC p.(Thr1082Ser), the only BS3 branch applicable to this missense variant at codon 1082 (within the codons 959-2129 beta-catenin binding domain).
• The BS3 RNA-assay branches are defined for synonymous/intronic variants and are not applicable to this missense change; no RNA-based benign functional evidence is therefore available or expected.
• No candidate functional-study publication was captured in the literature triage; a targeted search of the primary functional literature on APC beta-catenin-domain missense variants would be needed to close the gap.

Sources

Reasoning

Under the governing ClinGen InSiGHT APC VCEP v2.1 specification, BS4 (lack of segregation) is triggered by an affected family member who carries the disease but not the variant: an affected member without the variant scoring >=1 phenotype point, or at least two affected members without the variant each scoring >=0.5 phenotype points, is Strong, while a single affected member without the variant scoring >=0.5 phenotype points is Supporting. Applying BS4 therefore requires genotyped affected relatives who lack the variant and phenotype-point curation per VCEP Table 1. This case contains no proband, no pedigree, and no genotyped relatives at all, so there is no affected non-carrier to score. The only variant-level case report (PMID:25142776) describes a single affected carrier with no relatives studied, which can neither meet nor refute non-segregation. BS4 is therefore not assessed rather than not met.

Rule

APC VCEP v2.1 BS4: affected member without the variant scoring >=1 phenotype point, or >=2 affected members without the variant each scoring >=0.5 phenotype points = Strong; a single affected member without the variant scoring >=0.5 phenotype points = Supporting.

Evidence considered

• Governing framework: ClinGen InSiGHT APC VCEP v2.1 defines BS4 as Strong when an affected member without the variant scores >=1 phenotype point, or >=2 affected members without the variant each score >=0.5 phenotype points, and Supporting when a single affected member without the variant scores >=0.5 phenotype points (VCEP Table 1).
• The case was searched for affected relatives genotyped for this variant, and more generally for any non-segregation statement. No proband, pedigree, or genotyped relatives exist in the case files; the review is variant-level.
• PMID:25142776 reports one 52-year-old male colorectal cancer patient carrying the variant with no relatives studied; there is no affected non-carrier whose phenotype points could be counted.
• ClinVar submissions (which include Likely benign assertions) contain classification-level information only and no family genotypes; per the case rules, no criterion is inferred from another source's final classification.

Still missing

• No affected relative of the proband has been genotyped for c.3245C>G, so lack of segregation cannot be demonstrated.
• No phenotype-point curation (VCEP Table 1) for any unaffected-variant or affected-non-carrier relative is available.

Sources