Variant classification summary

NM_058216.3:c.30G>T

RAD51C · NP_478123.1:p.(Met10Ile) · NM_058216.3

GRCh37: chr17:56770034 G>T · GRCh38: chr17:58692673 G>T

Gene: RAD51C Transcript: NM_058216.3

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

RAD51C

Transcript

NM_058216.3

Protein

NP_478123.1:p.(Met10Ile)

gnomAD AF

6.194873370593432e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_058216.3:c.30G>T (p.Met10Ile) is a missense variant in exon 1 of RAD51C, a gene associated with autosomal dominant hereditary breast and ovarian cancer and autosomal recessive Fanconi anemia.

2

This variant is present at extremely low frequency in population databases: gnomAD v2.1 (1/251,450 alleles, AF=3.98e-6), gnomAD v4.1 (1/1,614,238 alleles, AF=6.19e-7), and absent from gnomAD-Canada, meeting PM2 at supporting level.

3

Multiple in silico predictors suggest a benign effect: REVEL score is 0.24 (below the typical pathogenic threshold of 0.5), BayesDel score is -0.112 (consistent with benign), and SpliceAI predicts no splicing impact (max delta=0.04). This meets BP4 at supporting benign level.

4

This variant has been reported in ClinVar as Uncertain significance by three clinical laboratories (ClinVar Variation ID: 538784). No expert panel has classified this variant as pathogenic or benign.

5

The ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel has published a specification document for RAD51C (Version 1.0.0), but the criterion-level rules are not yet structured for automated application. The generic ACMG/AMP 2015 framework was used as fallback.

6

No variant-specific functional studies, segregation data, de novo reports, or case-control analyses were identified for this exact variant. The comprehensive RAD51C functional screen by Hu et al. 2023 (PMID:37253112) tested 173 missense variants but did not include p.Met10Ile.

7

With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is indeterminate. This variant is classified as a Variant of Uncertain Significance (VUS) under generic 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.30G>T is a missense variant (p.Met10Ile) in exon 1. It does not fall into any null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). Under both the ClinGen SVI PVS1 framework (PMC6185798) and generic ACMG/AMP rules, PVS1 is not applicable to missense variants.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No alternative nucleotide change at codon 10 producing the same amino acid change (Met10Ile) has been established as pathogenic. The alternative nucleotide substitutions that would also yield Met10Ile (c.30G>C, c.30G>A) have no pathogenic classification in ClinVar or the literature.	clinvar
PS2	Not assessed	No de novo data available for this variant. No family studies or parent-of-origin testing reported in ClinVar or the literature.
PS3	Not assessed	No variant-specific functional studies of NM_058216.3:c.30G>T (p.Met10Ile) were identified. The comprehensive RAD51C functional screen by Hu et al. 2023 (PMID:37253112) tested 173 missense variants but did not include M10I. No other functional assay data were found in the literature or OncoKB.
PS4	Not assessed	No variant-specific case-control association data available. The Hu et al. 2023 case-control analysis of RAD51C deleterious missense variants did not include M10I. The Canadian cohort study (PMID:34326862) discussed RAD51C pathogenic variants at the gene level but did not report this specific variant.
PS5	Not assessed	No pathogenic variant has been established at the Met10 residue position of RAD51C. No different missense change at Met10 is classified as pathogenic in ClinVar or the literature.	clinvar pm5_candidates
PM1	Not met	Met10 lies in the N-terminal region of RAD51C (residue 1–83), which is structurally flexible and not part of any known critical functional domain. The pathogenic missense hotspot identified by Hu et al. 2023 maps to residues 125–168 (Walker A P-loop / ATP-binding region). Residue 10 is far from this hotspot and not in a functionally constrained domain.	PMID:37253112
PM2	Met	NM_058216.3:c.30G>T is present at extremely low frequency in population databases: gnomAD v2.1 (1/251,450 alleles, AF=3.98e-6), gnomAD v4.1 (1/1,614,238 alleles, AF=6.19e-7), and absent from gnomAD-Canada. These frequencies are well below the 0.1% PM2 threshold for a rare disease variant.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No candidate comparator variants at the same residue (Met10) with a different pathogenic missense change were identified. The automated PM5 candidate harvest found zero same-residue candidates, and manual review confirmed no known pathogenic variants at this position.	pm5_candidates clinvar
PM6	Not assessed	No de novo data available. PM6 requires confirmed de novo occurrence with maternity and paternity confirmed, which has not been reported for this variant.
PP1	Not assessed	No co-segregation data available. No family studies reporting segregation of this variant with disease in multiple affected family members were identified.
PP2	Not met	PP2 applies to genes with a low rate of benign missense variation where missense is a common disease mechanism. RAD51C has a substantial number of benign missense variants in gnomAD and does not meet the low-benign-missense-rate threshold. The Hu et al. 2023 study identified 135 neutral missense variants out of 173 tested, confirming that many RAD51C missense variants are functionally benign.	PMID:37253112 gnomad_v2 gnomad_v4
PP3	Not met	In silico predictors do not support a damaging effect. REVEL score is 0.24 (below typical pathogenic threshold of 0.5), BayesDel score is -0.112 (negative, suggesting benign), and SpliceAI max delta is 0.04 (no predicted splicing impact). Multiple lines of computational evidence do not support pathogenicity.	revel bayesdel spliceai
PP4	Not assessed	No patient-specific phenotype or family history data are available for this variant. The ClinVar submissions do not include detailed phenotype information.
PP5	Not met	No reputable source has classified this variant as pathogenic. ClinVar reports this variant as Uncertain significance (3 clinical laboratories, criteria provided, single submitter). No expert panel has classified it as pathogenic.	clinvar
BA1	Not met	The variant has an allele frequency far below the BA1 threshold (>1%). gnomAD v2.1 AF=0.0004%, gnomAD v4.1 AF=0.00006%. This variant is exceedingly rare, not common.	gnomad_v2 gnomad_v4
BS1	Not met	The variant frequency is far below the BS1 threshold (>0.3% for non-VCEP). gnomAD v2.1 AF=0.0004%, v4.1 AF=0.00006%. The variant is too rare to meet BS1.	gnomad_v2 gnomad_v4
BS2	Not assessed	No observation of this variant in a homozygous state or in trans with a pathogenic variant in a healthy adult. gnomAD reports 0 homozygotes, and no such observations were identified in the literature.
BS3	Not assessed	No variant-specific functional studies demonstrating no damaging effect were identified. The Hu et al. 2023 functional screen (PMID:37253112) did not include M10I. OncoKB reports Unknown Oncogenic Effect with no reviewed functional evidence.
BS4	Not assessed	No segregation data are available. No family studies reporting lack of segregation of this variant with disease were identified.
BP1	Not met	BP1 applies to missense variants in genes where primarily truncating variants cause disease. RAD51C has well-established pathogenic missense variants: Hu et al. 2023 identified 30 functionally deleterious missense variants in RAD51C, demonstrating that missense changes are a known pathogenic mechanism in this gene. BP1 does not apply.	PMID:37253112
BP2	Not assessed	No observation of this variant in trans with a known pathogenic variant in a healthy individual has been reported. RAD51C is associated with autosomal dominant hereditary breast/ovarian cancer; observation in trans with a pathogenic variant without disease would support a benign interpretation, but no such data exist.
BP4	Met	Multiple in silico predictors suggest a benign effect. BayesDel score is -0.112 (negative, consistent with benign), REVEL score is 0.24 (below pathogenic threshold of 0.5), and SpliceAI max delta is 0.04 (no splicing impact). Three independent computational tools converge on a non-damaging prediction.	revel bayesdel spliceai
BP5	Not assessed	No data available on whether this variant has been observed in a case with an alternate molecular basis for disease. No reports of co-occurrence with a known pathogenic variant in the same gene or another gene explaining the phenotype.
BP6	Not met	No reputable source has classified this variant as benign. ClinVar reports this variant as Uncertain significance. BP6 requires a reputable source to have reported the variant as benign without access to the primary evidence.	clinvar
BP7	N/A	NM_058216.3:c.30G>T is a missense variant (p.Met10Ile), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.

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