0%
RAD51Cc.145+1G>APathogenic
Print report
Variant interpretation report

RAD51C c.145+1G>A, p.?

NM_058216.2:c.145+1G>A NP_478123.1:p.? View identifiers
Classification
Pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.

Pathogenic.A pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About RAD51C

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is ClinGen RAD51C VCEP v1.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 3 Benign evidence criteria: 0
Pathogenic criteria applied · 3
PVS1Very strong
PVS1 · very strong

NM_058216.2:c.145+1G>A is a canonical splice donor variant affecting the +1 position of intron 1, disrupting the invariant GT dinucleotide. RAD51C loss of function is an established disease mechanism for autosomal dominant hereditary breast and ovarian cancer and autosomal recessive Fanconi anemia. SpliceAI predicts a strong splice-altering effect (max delta score 0.86). The variant is predicted to abolish normal RAD51C transcript expression, consistent with experimental data showing complete inactivation of the 5' splice site when the same canonical position is disrupted by a different nucleotide substitution (c.145+1G>T evaluated in Meindl et al. 2010). PVS1 is applied at very strong strength under the generic ACMG/ClinGen SVI PVS1 framework (PMC6185798).

PS3Supporting
PS3 · supporting

Meindl et al. (2010, PMID:20400964) experimentally characterized c.145+1G>T, a different nucleotide substitution at the same canonical +1 splice donor position. RT-PCR of patient leukocytes showed reduced normal RAD51C-001 transcript and increased nonfunctional RAD51C-008 transcript. A minigene splicing reporter assay in HeLa cells demonstrated complete inactivation of the mutant 5' splice site. LOH of the wild-type allele was confirmed in tumor tissue. Although the exact variant (G>A) was not directly tested, both G>T and G>A disrupt the invariant GT dinucleotide at the canonical +1 position, and the mechanism of splice disruption is identical. Supporting strength is applied because the exact variant was not tested but functional data on the same position strongly supports a deleterious splice effect.

PM2Moderate
PM2 · moderate

This variant is extremely rare in population databases. gnomAD v2.1 reports an allele frequency of 3.98e-6 (1/251,282 alleles, 0 homozygotes) and gnomAD v4.1 reports an allele frequency of 6.20e-7 (1/1,614,194 alleles, 0 homozygotes). Both are well below the PM2 threshold of <0.1%. The highest subpopulation frequency is in East Asian populations (v2.1: 5.44e-5; v4.1: 2.23e-5).

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAD51C Version 1.0 v1.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PS3 supporting, PM2 moderate; combination = 1 very strong + 1 moderate + 1 supporting, which maps to Pathogenic.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
1 / 1,614,194 alleles

gnomAD v4.1: 1 / 1,614,194 alleles. Recorded AF 6.19504e-07. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.97959e-06; MAF= 0.00040%, 1/251282 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.43774e-05; MAF= 0.00544%, 1/18390 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.860 maximum delta

Recorded SpliceAI maximum delta score: 0.860. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
5 reported laboratory submissions

4 Likely pathogenic · 1 Pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Context only ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

Applied · PS3 → OncoKB ↗
Somatic evidence
2 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV53616245, n = 2 times).

Context only COSMIC ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen RAD51C VCEP v1.0, with the data and sources behind each one.

29 criteria with recorded statuses: 3 met · 17 not met · 0 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_058216.2:c.145+1G>A is a canonical splice donor variant affecting the invariant +1 position of RAD51C intron 1, predicted to abolish normal splicing (SpliceAI delta 0.86). PVS1 is applied at very strong strength.

Functional studies of c.145+1G>T, a different nucleotide substitution at the same canonical +1 position, demonstrated complete inactivation of the 5' splice site in a minigene splicing reporter assay and loss of normal RAD51C transcript expression in patient leukocytes (Meindl et al., 2010). PS3 is applied at supporting strength.

This variant is extremely rare in population databases: gnomAD v2.1 AF = 3.98e-6 (1/251,282 alleles) and v4.1 AF = 6.20e-7 (1/1,614,194 alleles), with no homozygotes observed. PM2 is applied at moderate strength.

This variant has been reported in ClinVar (Variation ID 484741) as Likely pathogenic by four clinical laboratories and Pathogenic by one clinical laboratory, with review status of criteria provided, single submitter.

Met · 3

PVS1 Very strongNM_058216.2:c.145+1G>A is a canonical splice donor variant affecting the +1 position of intron 1, disrupting the invariant GT dinucleotide. RAD51C loss of function is an established disease mechanism for autosomal dominant hereditary breast and ovarian cancer and autosomal recessive Fanconi anemia. SpliceAI predicts a strong splice-altering effect (max delta score 0.86). The variant is predicted to abolish normal RAD51C transcript expression, consistent with experimental data showing complete inactivation of the 5' splice site when the same canonical position is disrupted by a different nucleotide substitution (c.145+1G>T evaluated in Meindl et al. 2010). PVS1 is applied at very strong strength under the generic ACMG/ClinGen SVI PVS1 framework (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Canonical +1 splice donor variant disrupting invariant GT dinucleotide
  • SpliceAI max delta score 0.86 predicts strong splice disruption
  • RAD51C loss of function is established germline disease mechanism
  • Experimental data for c.145+1G>T (same position
  • different substitution) demonstrates complete inactivation of the 5' splice site and loss of normal RAD51C transcript
Sources
pvs1_variant_assessmentpvs1_gene_contextspliceai ↗PMID:20400964 ↗
PS3 SupportingMeindl et al. (2010, PMID:20400964) experimentally characterized c.145+1G>T, a different nucleotide substitution at the same canonical +1 splice donor position. RT-PCR of patient leukocytes showed reduced normal RAD51C-001 transcript and increased nonfunctional RAD51C-008 transcript. A minigene splicing reporter assay in HeLa cells demonstrated complete inactivation of the mutant 5' splice site. LOH of the wild-type allele was confirmed in tumor tissue. Although the exact variant (G>A) was not directly tested, both G>T and G>A disrupt the invariant GT dinucleotide at the canonical +1 position, and the mechanism of splice disruption is identical. Supporting strength is applied because the exact variant was not tested but functional data on the same position strongly supports a deleterious splice effect. Details ▾Hide ▴
Evidence considered
  • c.145+1G>T experimentally shown to inactivate 5' splice site by RT-PCR and minigene splicing reporter assay
  • Complete loss of normal RAD51C-001 transcript
  • increased nonfunctional RAD51C-008
  • LOH of wild-type allele in tumor tissue from carrier
  • Both G>T and G>A disrupt the canonical GT dinucleotide at +1 position
Still missing
  • Exact variant NM_058216.2:c.145+1G>A has not been directly tested in functional assays
Sources
PMID:20400964 ↗
PM2 ModerateThis variant is extremely rare in population databases. gnomAD v2.1 reports an allele frequency of 3.98e-6 (1/251,282 alleles, 0 homozygotes) and gnomAD v4.1 reports an allele frequency of 6.20e-7 (1/1,614,194 alleles, 0 homozygotes). Both are well below the PM2 threshold of <0.1%. The highest subpopulation frequency is in East Asian populations (v2.1: 5.44e-5; v4.1: 2.23e-5). Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: AF = 3.98e-6 (1/251
  • 282)
  • 0 homozygotes
  • gnomAD v4.1: AF = 6.20e-7 (1/1
  • 614
  • 194)
  • Highest subpopulation AF: East Asian 5.44e-5 (v2.1)
  • well below 0.1% threshold
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 17 · evaluated, threshold not reached

PS2 No de novo occurrence data is available for this variant. No published report of a confirmed de novo observation was identified in the literature or ClinVar submissions. Details ▾Hide ▴
Still missing
  • No de novo testing data available
PS4 No case-control study with statistical significance has been published for NM_058216.2:c.145+1G>A specifically. The variant is present in ClinVar with 5 clinical laboratory submissions (4 Likely pathogenic, 1 Pathogenic), but these do not constitute a controlled case-control comparison. The Meindl et al. study reported c.145+1G>T (not G>A) in 1 of 480 BC/OC pedigrees. Details ▾Hide ▴
Evidence considered
  • ClinVar: 5 submissions (4 Likely pathogenic
  • 1 Pathogenic) but no controlled prevalence data
  • Meindl et al. 2010 reported c.145+1G>T in 1/480 BC/OC pedigrees
  • not c.145+1G>A
Still missing
  • No case-control study with odds ratio for this specific variant
Sources
clinvar ↗
PM1 The variant is a canonical splice donor site at the exon 1/intron 1 boundary. No specific mutational hotspot or well-characterized critical functional domain has been identified at this splice junction position. The variant disrupts splicing rather than targeting a defined protein domain. Cancerhotspots.org does not list this position as a significant residue. Details ▾Hide ▴
Evidence considered
  • Not located in a known mutational hotspot or critical functional domain
  • Cancerhotspots.org: no significant residue at this position
  • Position is a splice junction
  • not a missense in a characterized domain
PM6 No de novo occurrence has been reported for this variant. PM6 requires a confirmed de novo observation with both maternity and paternity confirmed. No such data was identified in ClinVar submissions or the reviewed literature. Details ▾Hide ▴
Still missing
  • No de novo testing data available
PP1 No segregation data is available for NM_058216.2:c.145+1G>A. Meindl et al. (2010) reported segregation of c.145+1G>T in one family (three sisters with breast/ovarian cancer), but this is a different nucleotide substitution. No segregation analysis has been published for c.145+1G>A specifically. Details ▾Hide ▴
Evidence considered
  • Meindl et al. 2010: segregation of c.145+1G>T in one pedigree
  • not c.145+1G>A
Still missing
  • No segregation data for this specific variant
Sources
PMID:20400964 ↗
PP3 While SpliceAI (max delta 0.86) and BayesDel (0.66) predict a deleterious effect, the splice prediction evidence is already captured by PVS1 for this canonical splice variant. Under ClinGen SVI PVS1 recommendations (PMC6185798) and standard ACMG/AMP practice, PP3 should not be double-counted for the same splice-effect prediction evidence that supports PVS1. PP3 is therefore not applied to avoid evidence stacking. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.86 predicts strong splice disruption
  • BayesDel score 0.66 predicts deleterious effect
  • In silico splice evidence already captured by PVS1
  • double-counting avoided per PVS1 decision tree
Sources
spliceai ↗bayesdel
PP4 No patient phenotype or family history data is available for adjudication. The variant is reported in ClinVar as Likely pathogenic/Pathogenic by clinical testing laboratories, but specific phenotype details are not provided in the available data. PP4 requires that the patient's phenotype or family history is highly specific for the disease associated with the gene. Details ▾Hide ▴
Evidence considered
  • Clinical laboratories report variant as Likely pathogenic/Pathogenic but specific phenotype data not available
Still missing
  • No patient phenotype or family history details available for review
Sources
clinvar ↗
PP5 PP5 requires a reputable source (e.g., ClinGen expert panel, 3-star ClinVar review status) to have classified the variant as pathogenic. The ClinVar record (Variation ID 484741) has review status 'criteria provided, single submitter' (1-star), consisting of 5 individual clinical laboratory submissions. No expert panel review has been performed. Under the adjudication rule, PP5 is applied at supporting strength only when ClinVar review status is 3-star expert panel, which is not met here. Details ▾Hide ▴
Evidence considered
  • ClinVar Variation ID 484741: 4 Likely pathogenic
  • 1 Pathogenic submissions
  • Review status: criteria provided
  • single submitter (1-star
  • not 3-star expert panel)
Still missing
  • No expert panel review available
Sources
clinvar ↗
BA1 The allele frequency in gnomAD is well below the BA1 threshold of >1%. gnomAD v2.1 AF = 3.98e-6 (0.0004%) and v4.1 AF = 6.20e-7 (0.00006%). This variant is extremely rare, not common. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: AF = 0.0004%
  • gnomAD v4.1: AF = 0.00006%
  • Both well below 1% BA1 threshold
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The allele frequency in gnomAD is well below the BS1 threshold of >0.3%. gnomAD v2.1 AF = 3.98e-6 (0.0004%) and v4.1 AF = 6.20e-7 (0.00006%). The variant is significantly rarer than expected for a benign polymorphism. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: AF = 0.0004%
  • gnomAD v4.1: AF = 0.00006%
  • Both well below 0.3% BS1 threshold
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No data is available showing this variant observed in healthy adults with full penetrance expected. The single gnomAD observation (East Asian, v2.1 exomes) lacks clinical phenotype confirmation and penetrance data. BS2 requires observation in a healthy adult individual where the disease is fully penetrant at an early age, which cannot be confirmed from population database allele counts alone. Details ▾Hide ▴
Still missing
  • No confirmed healthy adult carriers with full penetrance expectation
BS3 BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing. The available functional data for the same splice position (c.145+1G>T in Meindl et al. 2010) demonstrates a damaging effect: complete inactivation of the 5' splice site, reduced normal transcript, and LOH in tumor tissue. The evidence points toward a deleterious effect rather than a benign one. Details ▾Hide ▴
Evidence considered
  • Meindl et al. 2010: c.145+1G>T causes complete 5' splice site inactivation in minigene assay
  • Functional data supports deleterious effect
  • not benign
Sources
PMID:20400964 ↗
BS4 No segregation data is available for NM_058216.2:c.145+1G>A showing lack of co-segregation with disease. The only published segregation data involves c.145+1G>T (Meindl et al. 2010) which showed co-segregation with disease, not lack of segregation. Details ▾Hide ▴
Evidence considered
  • No non-segregation data for c.145+1G>A
Still missing
  • No segregation data for this specific variant
Sources
PMID:20400964 ↗
BP2 No data available showing this variant observed in trans with a known pathogenic variant or in cis with a pathogenic variant in a recessive disorder. RAD51C has both autosomal dominant (HBOC) and autosomal recessive (Fanconi anemia) inheritance patterns, but no phase data is available for this variant. Details ▾Hide ▴
Still missing
  • No phase data with other RAD51C variants available
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product. Both SpliceAI (max delta 0.86) and BayesDel (0.66) predict a deleterious effect. The in silico evidence suggests a damaging impact on splicing, not a benign one. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.86 predicts strong splice disruption
  • BayesDel score 0.66 predicts deleterious effect
  • Both predictions are damaging
  • not benign
Sources
spliceai ↗bayesdel
BP5 No data available showing this variant found in a case with an alternative molecular basis for disease. BP5 requires observation in an individual with a clear alternate genetic cause for their phenotype. Details ▾Hide ▴
Still missing
  • No alternate molecular cause data available
BP6 BP6 requires a reputable source (3-star ClinVar expert panel) to have classified the variant as benign or likely benign. The ClinVar record (Variation ID 484741) shows Likely pathogenic/Pathogenic classifications from clinical laboratories. No benign classification exists from any source. Details ▾Hide ▴
Evidence considered
  • ClinVar Variation ID 484741: consensus Likely pathogenic/Pathogenic
  • No benign or likely benign classifications from any source
Sources
clinvar ↗
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to missense variants with a different amino acid change at the same residue as a known pathogenic missense variant. This is a canonical splice site variant, not a missense substitution. Details ▾Hide ▴

No further detail was recorded.

PM3 N/APM3 applies to variants observed in trans with a pathogenic variant in a recessive disorder. No phase data available; assessed as trivially not_applicable per adjudication instructions. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to protein length changes due to in-frame deletions/insertions or stop-loss variants. This is a single nucleotide substitution at a canonical splice site. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 applies to missense variants where a different pathogenic missense change has been identified at the same amino acid residue. This is a canonical splice site variant (c.145+1G>A), not a missense substitution. No same-residue missense comparator can be identified from the variant consequence. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 applies when a missense variant occurs in a gene with a low rate of benign missense variation and where missense variants are a common disease mechanism. This is a canonical splice site variant, not a missense substitution. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies when a missense variant occurs in a gene where truncating variants are a known disease mechanism and only truncating variants are pathogenic. This is a canonical splice site variant, not a missense substitution. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions without a known function. This is a single nucleotide substitution at a canonical splice site. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous (silent) variants with no predicted impact on splicing. This is a canonical +1 splice donor variant with strong SpliceAI prediction (delta 0.86), which is definitively predicted to alter splicing. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 applies to the same variant identified in multiple patients with a specific phenotype. This criterion was not included in the assess list. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
RAD51C
Transcript
NM_058216.2
Coding (HGVS c.)
NM_058216.2:c.145+1G>A
Protein (HGVS p.)
NP_478123.1:p.?
GRCh38
chr17:58692789 G>A
GRCh37
chr17:56770150 G>A
ClinVar
484741
COSMIC
COSV53616245

Gene diagram

Every interpreted variant in RAD51C, mapped onto the exon structure of NM_058216.2. Select a row to find it on the plot.

RAD51CNM_058216.2
Fetching transcript structure from UCSC…
gnomAD v4.1 1 / 1,614,194 alleles AF 6.2e-07 · 0 homozygotes
gnomAD v2.1 1 / 251,282 alleles AF 3.98e-06 · 0 homozygotes
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6.2e-07 · 1 / 1,614,194 alleles · 0 hom
East Asian1 / 44,884 2.2e-05
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish).

gnomAD v2.1

AF 4e-06 · 1 / 251,282 alleles · 0 hom
East Asian1 / 18,390 5.4e-05
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.19504e-07; MAF= 0.00006%, 1/1614194 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.22797e-05; MAF= 0.00223%, 1/44884 alleles, homozygotes = 0).

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.97959e-06; MAF= 0.00040%, 1/251282 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.43774e-05; MAF= 0.00544%, 1/18390 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +83 bp
0.000
SpliceAI acceptor gainat -81 bp
0.000
SpliceAI donor lossat -1 bp
0.860
SpliceAI donor gainat +170 bp
0.200
Pangolin splice lossmagnitude shown
-0.660
Pangolin splice gain
0.110

Other predictors

REVEL
Not available
BayesDel
0.660

How the predictions were used

PP3 While SpliceAI (max delta 0.86) and BayesDel (0.66) predict a deleterious effect, the splice prediction evidence is already captured by PVS1 for this canonical splice variant. Under ClinGen SVI PVS1 recommendations (PMC6185798) and standard ACMG/AMP practice, PP3 should not be double-counted for the same splice-effect prediction evidence that supports PVS1. PP3 is therefore not applied to avoid evidence stacking. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.86 predicts strong splice disruption
  • BayesDel score 0.66 predicts deleterious effect
  • In silico splice evidence already captured by PVS1
  • double-counting avoided per PVS1 decision tree
Sources
spliceai ↗bayesdel
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product. Both SpliceAI (max delta 0.86) and BayesDel (0.66) predict a deleterious effect. The in silico evidence suggests a damaging impact on splicing, not a benign one. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.86 predicts strong splice disruption
  • BayesDel score 0.66 predicts deleterious effect
  • Both predictions are damaging
  • not benign
Sources
spliceai ↗bayesdel
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted impact on splicing. This is a canonical +1 splice donor variant with strong SpliceAI prediction (delta 0.86), which is definitively predicted to alter splicing. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.86). BayesDel score = 0.66.

4 paper records listed. 1 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.

Cited in the classification

  • Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene.
    Meindl A et al. · 2010 May
    Meindl et al. (2010) identified six pathogenic germline RAD51C mutations in 480 German breast/ovarian cancer pedigrees, including the splice donor mutation c.145+1G>T (not c.145+1G>A). Functional characterization by RT-PCR and minigene splicing reporter assay demonstrated complete inactivation of the 5' splice site, reduced normal RAD51C-001 transcript, and increased nonfunctional RAD51C-008 transcript. LOH of the wild-type allele was confirmed in tumor tissue from a carrier. This study establishes RAD51C as a cancer susceptibility gene but does not report or evaluate NM_058216.2:c.145+1G>A.
    → PVS1 → PS3 Does not name this variant
    PMID 20400964 ↗
    Source detail
    The splice donor mutation (145+1G>T) presents in a family with three sisters affected by breast or ovarian cancers (Fig. 1c) and disrupts the canonical GT dinucleotide.

    Location Results, Table 1, Figure 1c, Figure 2a-d; Online Methods

    Context RT-PCR of patient peripheral blood leukocytes; minigene splicing reporter assay in HeLa cells; RAD51 foci immunofluorescence in human fibroblasts; complementation in Rad51c-deficient DT40 chicken cells

Other recorded publications

  • Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
    Richards S et al. · 2015
    Richards et al. (2015) present the ACMG/AMP standards and guidelines for interpretation of sequence variants. This is a general methodological guideline that does not discuss any specific RAD51C variant or any specific variant at all. NM_058216.2:c.145+1G>A is not mentioned.
    Does not name this variant
    PMID 25741868 ↗
  • Fanconi Anemia.
    Adam MP et al. · 1993
    Meindl et al. (2010) report on Fanconi anemia as a GeneReview entry. This is a general clinical resource on Fanconi anemia that does not mention the specific variant NM_058216.2:c.145+1G>A. No abstract or full text with variant-specific information was available for review.
    Does not name this variant
    PMID 20301575 ↗
  • A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
    Hampel H et al. · 2015
    Hampel et al. (2015) present ACMG/NSGC practice guidelines for cancer predisposition referral indications. This is a clinical referral guideline that lists hereditary cancer syndromes and criteria for genetic counseling referral. NM_058216.2:c.145+1G>A is not mentioned or discussed.
    Does not name this variant
    PMID 25394175 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 1 / 1,614,194 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.860 Open source ↗
ClinVar 4 Likely pathogenic · 1 Pathogenic Open source ↗
COSMIC Captured COSMIC source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.19504e-07; MAF= 0.00006%, 1/1614194 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.22797e-05; MAF= 0.00223%, 1/44884 alleles, homozygotes = 0).

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.97959e-06; MAF= 0.00040%, 1/251282 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.43774e-05; MAF= 0.00544%, 1/18390 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Likely pathogenic (4 clinical laboratories) and as Pathogenic (1 clinical laboratory). (ClinVarID = 484741)

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.86). BayesDel score = 0.66.

Somatic

This variant has previously been reported in somatic cancers (COSMIC; COSV53616245, n = 2 times).