NM_058216.3:c.431T>C

RAD51C · NP_478123.1:p.(Ile144Thr) · NM_058216.3

GRCh37: chr17:56774080 T>C · GRCh38: chr17:58696719 T>C

Gene: RAD51C Transcript: NM_058216.3

Final call

VUS

PM2 supporting BP6 supporting

Variant details

Gene

RAD51C

Transcript

NM_058216.3

Protein

NP_478123.1:p.(Ile144Thr)

gnomAD AF

0.00014187508054043873 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_058216.3:c.431T>C (p.Ile144Thr) in RAD51C is a rare missense variant with extremely low population frequency (gnomAD v2.1 AF=0.0057%, v4.1 AF=0.014%). The ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel has published RAD51C specifications (version 1.0.0) but no per-criterion rules were available for direct application; generic ACMG/AMP 2015 criteria were used as fallback.

The variant is absent or at extremely low frequency in population databases, meeting PM2 at supporting strength (gnomAD v4.1 overall AF=0.014%; 0 homozygotes). gnomAD v4.1 Middle Eastern subpopulation AF=0.279% is noted but remains below the BS1 threshold of 0.3%.

Myriad Genetics classified this variant as Likely benign (SCV004019909, criteria provided), meeting BP6 at supporting strength. However, the cited reference (PMID:25085752) is a BRCA1/BRCA2 reclassification algorithm and does not provide RAD51C-specific evidence.

In silico predictions are inconclusive: REVEL 0.314, BayesDel 0.041, SpliceAI delta 0.01, with Polyphen-2/SIFT suggesting possible damage but SNPs&GO predicting neutrality (PMID:23117857). Neither PP3 nor BP4 is met.

The variant has been observed in one Iraqi Jewish breast cancer proband (PMID:23117857) and one Danish HBOC family (PMID:26740214) but at insufficient frequency for PS4. No functional studies (PS3/BS3), segregation data (PP1/BS4), or de novo observations (PS2/PM6) are available.

The variant is not located in a statistically significant hotspot (PM1 not met), no alternative nucleotide changes at the same residue are established as pathogenic (PM5 not applicable), and RAD51C is not a gene with a low rate of benign missense variation (PP2 not met).

Overall classification: Uncertain significance. One supporting pathogenic criterion (PM2) is balanced by one supporting benign criterion (BP6), with all other criteria either not met or not applicable. This results in indeterminate classification under ACMG/AMP 2015 combination rules.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_058216.3:c.431T>C is a missense variant (p.Ile144Thr) and does not fall into any null-variant category (nonsense, frameshift, canonical splice). Not eligible for PVS1 under generic ACMG/AMP or ClinGen SVI PVS1 framework.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No evidence that the same amino acid change (p.Ile144Thr) has been established as pathogenic via a different nucleotide change. No alternative nucleotide substitutions at codon 144 were identified in ClinVar or the literature.	clinvar pm5_candidates
PS2	Not met	No de novo observation (maternity and paternity confirmed) has been reported for NM_058216.3:c.431T>C in any reviewed publication or ClinVar submission.
PS3	Not met	No variant-specific functional studies (e.g., HR assay, protein interaction, cellular sensitivity) have been reported for p.Ile144Thr in any reviewed publication. OncoKB did not identify any variant-specific reviewed functional evidence.	oncokb
PS4	Not met	The variant has been observed in affected individuals but at insufficient frequency and without controlled case-control comparison to reach statistical significance. One Iraqi Jewish proband with breast cancer (PMID:23117857; absent in 60 matched controls) and one Danish HBOC family (PMID:26740214). The aggregate data do not meet PS4 thresholds.	PMID:23117857 PMID:26740214 clinvar
PS5	Not met	No data available. This criterion requires a variant to be identified as likely pathogenic by a reputable source without access to the primary data — not applicable here.
PM1	Not met	p.Ile144 is not located in a statistically significant mutational hotspot or a well-established critical functional domain for RAD51C. Hotspot analysis returned negative.
PM2	Met	NM_058216.3:c.431T>C is at extremely low frequency in population databases. gnomAD v2.1: AF=0.00566% (16/282,878 alleles, 0 homozygotes). gnomAD v4.1: AF=0.01419% (229/1,614,096 alleles, 0 homozygotes). Both overall frequencies are well below the 0.1% threshold. No homozygotes observed. Note: gnomAD v4.1 grpmax FAF=0.178% and Middle Eastern subpopulation AF=0.279%, which slightly moderates the strength but remains below the BS1 threshold of 0.3%.	gnomad_v2 gnomad_v4
PM5	N/A	No pathogenic comparator variants at the same amino acid residue (Ile144) were identified. Automated PM5 candidate harvesting did not find any same-residue pathogenic missense changes.	pm5_candidates
PM6	Not met	No de novo observation with confirmed maternity and paternity has been reported for this variant.
PP1	Not met	No segregation data available. The one family reported in PMID:23117857 (Iraqi Jewish proband with mother and sister affected) could not undergo co-segregation analysis because both relatives were deceased.	PMID:23117857
PP2	Not met	RAD51C is not established as a gene with a low rate of benign missense variation. Both pathogenic and neutral missense variants are documented in the literature and ClinVar. Criterion not met.	clinvar
PP3	Not met	In silico predictions are mixed and do not converge on a damaging effect. REVEL score 0.314 (below typical pathogenicity threshold of 0.5). BayesDel score 0.0405 (very low). SpliceAI max delta 0.01 (no splice impact). While Polyphen-2 and SIFT predicted possibly deleterious (PMID:23117857), SNPs&GO predicted neutral, and Align-GVGD gave C25 (borderline, PMID:26740214). The overall in silico profile does not support PP3.	revel bayesdel spliceai PMID:23117857 PMID:26740214
PP4	N/A	No proband phenotype was provided for adjudication. PP4 requires the patient's phenotype or family history to be highly specific for the disease associated with RAD51C.
PP5	Not met	No reputable source (e.g., expert panel, clinical laboratory with multi-criteria review) has classified this variant as pathogenic or likely pathogenic. ClinVar reports it as Uncertain significance (18 labs).	clinvar
BA1	Not met	The variant is not common. Maximum subpopulation AF in gnomAD v4.1 is 0.279% (Middle Eastern), well below the 1% BA1 threshold. Overall AF across all populations is <0.015%.	gnomad_v2 gnomad_v4
BS1	Not met	The variant does not exceed the 0.3% population frequency threshold. The highest subpopulation frequency is 0.279% in gnomAD v4.1 Middle Eastern, which is just below 0.3%. Overall AF is much lower (0.014%).	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous individuals observed in gnomAD v2.1 (0/282,878) or gnomAD v4.1 (0/1,614,096). Absence of homozygotes does not provide evidence for a benign effect in an autosomal dominant disease gene where homozygosity is not expected in healthy populations.	gnomad_v2 gnomad_v4
BS3	Not met	No functional studies have been reported demonstrating that p.Ile144Thr has no deleterious effect on protein function or splicing.
BS4	Not met	No segregation data available to demonstrate lack of co-segregation with disease. The one family reported (PMID:23117857) had affected relatives but co-segregation analysis was not possible.	PMID:23117857
BP1	N/A	RAD51C disease is not caused exclusively by truncating variants. Pathogenic missense variants in RAD51C are well documented (e.g., p.Gln143Arg, p.Arg258His), so BP1 does not apply.	PMID:26740214
BP2	Not met	No data available on observation of this variant in trans with a known pathogenic RAD51C variant.
BP3	N/A	Skipped by user instruction: trivially not_applicable (in-frame deletion/insertion in non-repetitive region; this is a missense substitution).
BP4	Not met	Multiple lines of in silico evidence are not consistently benign. REVEL 0.314 is below the typical pathogenic threshold but not clearly benign. BayesDel 0.0405 is very low and supportive of a benign interpretation. However, Polyphen-2 and SIFT predicted possibly deleterious (PMID:23117857). The overall computational evidence is mixed rather than consistently benign, and does not meet BP4.	revel bayesdel PMID:23117857 PMID:26740214
BP5	Not met	No data available. This criterion requires the variant to be found in a case with an alternative molecular basis for disease, and no such information has been reported.
BP6	Met	Myriad Genetics, Inc. (SCV004019909) classified this variant as Likely benign with criteria provided. This represents a reputable clinical laboratory asserting a benign interpretation. While only a single submitter, it meets BP6 at supporting level.	clinvar
BP7	N/A	NM_058216.3:c.431T>C is a missense variant (p.Ile144Thr), not a synonymous variant. BP7 applies only to synonymous (silent) variants with no predicted splice impact.

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