BRCA2c.5946delPathogenic

Print report

Variant interpretation report

BRCA2 c.5946del, p.(Ser1982ArgfsTer22)

NM_000059.4:c.5946del NP_000050.3:p.(Ser1982ArgfsTer22) 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 BRCA2

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 supporting (benign) · 1 very strong (pathogenic) · 2 strong (pathogenic) · 1 supporting (pathogenic)
Expert rules: ClinGen BRCA2 VCEP v1.2.0
Other laboratories (ClinVar): 67 Pathogenic · 1 pathogenic
Pipeline record: 7 Jun 2026

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): NM_000059.4:c.5946del is a frameshift deletion in BRCA2 exon 11 predicted to cause a premature termination codon (p.Ser1982ArgfsTer22) with expected nonsense-mediated decay. Loss of function is an established disease mechanism for BRCA2 in hereditary breast and ovarian cancer. Per ENIGMA Specifications Table 4, BRCA2 exon 11 PTC variants are assigned PVS1 at very strong weight; the variant occurs upstream of the DNA-binding domain (aa 2481-3186) and is not in a PVS1-downgraded region.
PM5 (strong): This is a protein termination codon (PTC) variant in BRCA2 exon 11. Per ENIGMA Specifications Table 4, exon 11 is assigned PM5_Strong (PTC), indicating that other proven pathogenic PTC variants have been previously observed in this exon. The variant qualifies for PVS1 and PM5_PTC provides additional weight.
PP4 (strong): Clinical-history likelihood ratio from Li et al. 2020 (PMID:31853058) is LR=31.79 based on 149 probands. This exceeds the ENIGMA PP4_Strong threshold of ≥18.7:1, indicating that the personal and family cancer history profile of carriers is significantly enriched for pathogenicity.
PP5 (supporting): Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic.
BS1 (supporting): ENIGMA BS1_Supporting applies when FAF > 0.002% and ≤0.01% in gnomAD non-founder populations. The grpmax FAF is 5.39e-05 (0.00539%) in gnomAD v2.1, which falls within this range. The variant is observed in outbred population controls at a low but non-negligible frequency, providing supporting evidence that it may be more common than expected for a highly penetrant pathogenic variant.

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 BRCA2 VCEP v1.2.0. 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: 4 Benign evidence criteria: 1

Pathogenic criteria applied · 4

PVS1Very strong

PVS1 · very strong

NM_000059.4:c.5946del is a frameshift deletion in BRCA2 exon 11 predicted to cause a premature termination codon (p.Ser1982ArgfsTer22) with expected nonsense-mediated decay. Loss of function is an established disease mechanism for BRCA2 in hereditary breast and ovarian cancer. Per ENIGMA Specifications Table 4, BRCA2 exon 11 PTC variants are assigned PVS1 at very strong weight; the variant occurs upstream of the DNA-binding domain (aa 2481-3186) and is not in a PVS1-downgraded region.

PM5Strong

PM5 · strong

This is a protein termination codon (PTC) variant in BRCA2 exon 11. Per ENIGMA Specifications Table 4, exon 11 is assigned PM5_Strong (PTC), indicating that other proven pathogenic PTC variants have been previously observed in this exon. The variant qualifies for PVS1 and PM5_PTC provides additional weight.

PP4Strong

PP4 · strong

Clinical-history likelihood ratio from Li et al. 2020 (PMID:31853058) is LR=31.79 based on 149 probands. This exceeds the ENIGMA PP4_Strong threshold of ≥18.7:1, indicating that the personal and family cancer history profile of carriers is significantly enriched for pathogenicity.

PP5Supporting

PP5 · supporting

Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic.

Benign criteria applied · 1

BS1Supporting

BS1 · supporting

ENIGMA BS1_Supporting applies when FAF > 0.002% and ≤0.01% in gnomAD non-founder populations. The grpmax FAF is 5.39e-05 (0.00539%) in gnomAD v2.1, which falls within this range. The variant is observed in outbred population controls at a low but non-negligible frequency, providing supporting evidence that it may be more common than expected for a highly penetrant pathogenic variant.

Recorded classification: Pathogenic

ENIGMA BRCA1/BRCA2 v1.2.0 Table 3 point system (+16: PVS1+8, PM5+4, PP4+4, PP5+1, BS1-1) meets pathogenic threshold >=10; all_of rule 1 Very Strong + >=1 Strong also independently satisfied.

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

225 / 1,613,878 alleles

gnomAD v4.1: 225 / 1,613,878 alleles. Recorded AF 0.000139416. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000276509; MAF= 0.02765%, 78/282088 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00588576; MAF= 0.58858%, 61/10364 alleles, homozygotes = 0); grpmax FAF= 5.39e-05.

Applied · BS1 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗

ClinVar submissions

68 reported laboratory submissions

67 Pathogenic · 1 pathogenic.

Applied · PP5 → ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

10 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV66447676, n = 10 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under ClinGen BRCA2 VCEP v1.2.0, with the data and sources behind each one.

28 criteria with recorded statuses: 5 met · 3 not met · 6 not assessed · 14 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_000059.4:c.5946del is a frameshift deletion in BRCA2 exon 11 resulting in a premature termination codon (p.Ser1982ArgfsTer22) with expected nonsense-mediated decay, in a gene where loss of function is an established mechanism for hereditary breast and ovarian cancer. Per ENIGMA Specifications Table 4, BRCA2 exon 11 PTC variants are assigned PVS1 at very strong weight.

ENIGMA Specifications Table 4 assigns PM5_Strong (PTC) to BRCA2 exon 11, indicating additional pathogenic weight for a protein termination codon variant in an exon where other proven pathogenic PTC variants have been previously observed.

Clinical-history likelihood ratio analysis from Li et al. 2020 (PMID:31853058) yields an LR of 31.79 based on 149 carriers, exceeding the ENIGMA PP4_Strong threshold of ≥18.7:1. The personal and family cancer history profile of individuals carrying this variant is significantly enriched for breast and ovarian cancer compared to non-carriers.

The variant is present in gnomAD population databases at low frequency in non-founder populations (grpmax FAF=5.39e-05 in v2.1, 2.154e-05 in v4.1), meeting ENIGMA BS1_Supporting (FAF >0.002% and ≤0.01%). The higher Ashkenazi Jewish allele frequency (0.589%) is attributable to a known founder effect and is excluded from BS1/BA1 assessment per ENIGMA non-founder population rules.

This variant has been reported in ClinVar as Pathogenic by 67 clinical laboratories and by the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel (ClinVar Variation ID: 9325). The variant has been observed in multiple affected individuals across diverse populations and has been described as a recurrent pathogenic founder mutation.

Under ENIGMA Table 3 combining rules, the combination of PVS1 (Very Strong) + PM5 (Strong) satisfies the Pathogenic classification threshold (1 Very Strong + ≥1 Strong). PP4 (Strong) provides additional corroborating evidence. BS1_Supporting does not alter the pathogenic classification.

Met · 5

PVS1 Very strongNM_000059.4:c.5946del is a frameshift deletion in BRCA2 exon 11 predicted to cause a premature termination codon (p.Ser1982ArgfsTer22) with expected nonsense-mediated decay. Loss of function is an established disease mechanism for BRCA2 in hereditary breast and ovarian cancer. Per ENIGMA Specifications Table 4, BRCA2 exon 11 PTC variants are assigned PVS1 at very strong weight; the variant occurs upstream of the DNA-binding domain (aa 2481-3186) and is not in a PVS1-downgraded region. Details ▾Hide ▴

Evidence considered

Frameshift deletion (c.5946del) producing p.Ser1982ArgfsTer22 in BRCA2 exon 11
ENIGMA Table 4 assigns PVS1 at very strong weight for BRCA2 E11 PTC variants
NMD expected
variant is upstream of clinically important DNA-binding domain (aa 2481-3186)
BRCA2 germline LOF is an established disease mechanism (ClinGen ENIGMA VCEP v1.2.0)

Sources

vcep_specifications_table4_v1_2_2024_11_18cspec ↗pvs1_generic_framework ↗

PM5 StrongThis is a protein termination codon (PTC) variant in BRCA2 exon 11. Per ENIGMA Specifications Table 4, exon 11 is assigned PM5_Strong (PTC), indicating that other proven pathogenic PTC variants have been previously observed in this exon. The variant qualifies for PVS1 and PM5_PTC provides additional weight. Details ▾Hide ▴

Evidence considered

ENIGMA Table 4: BRCA2 E11 assigned PM5_Strong (PTC)
E11 is not a PM5_N/A exon (PM5_N/A exons: E12
E27
E6)
Multiple proven pathogenic PTC variants exist in BRCA2 exon 11

Sources

vcep_specifications_table4_v1_2_2024_11_18cspec ↗

PP4 StrongClinical-history likelihood ratio from Li et al. 2020 (PMID:31853058) is LR=31.79 based on 149 probands. This exceeds the ENIGMA PP4_Strong threshold of ≥18.7:1, indicating that the personal and family cancer history profile of carriers is significantly enriched for pathogenicity. Details ▾Hide ▴

Evidence considered

Li et al. 2020 clinical-history LR = 31.79 (149 probands)
Exceeds PP4_Strong threshold of LR ≥18.7:1
Personal/family cancer history profile consistent with pathogenic BRCA2 variant

Sources

vcep_pmid_31853058_brca2_clinical_history_lrPMID:31853058 ↗31853058

PP5 SupportingExpert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic. Details ▾Hide ▴

Evidence considered

ClinVar expert panel classification

Sources

clinvar ↗

BS1 SupportingENIGMA BS1_Supporting applies when FAF > 0.002% and ≤0.01% in gnomAD non-founder populations. The grpmax FAF is 5.39e-05 (0.00539%) in gnomAD v2.1, which falls within this range. The variant is observed in outbred population controls at a low but non-negligible frequency, providing supporting evidence that it may be more common than expected for a highly penetrant pathogenic variant. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 grpmax FAF = 5.39e-05 (0.00539%)
meets BS1_Supporting range (>0.002%
≤0.01%)
gnomAD v4.1 grpmax FAF = 2.154e-05 (0.00215%)
meets BS1_Supporting range
0 homozygotes in both gnomAD versions

Sources

gnomad_v2 ↗gnomad_v4 ↗

Not met · 3 · evaluated, threshold not reached

PM2 ENIGMA PM2_Supporting requires absence from gnomAD v2.1 (non-cancer, exome) and gnomAD v3.1 (non-cancer) in outbred populations. This variant is present in gnomAD v2.1 (AF=0.02765%, 78/282088 alleles) and gnomAD v4.1 (AF=0.01394%, 225/1613878 alleles), including presence in non-founder populations (grpmax FAF=5.39e-05 in v2.1). PM2 is therefore not met. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: 78/282088 alleles (AF=0.02765%)
grpmax FAF=5.39e-05
gnomAD v4.1: 225/1613878 alleles (AF=0.01394%)
grpmax FAF=2.154e-05
Variant is present in outbred populations
PM2 absent-from-controls threshold not satisfied

Sources

gnomad_v2 ↗gnomad_v4 ↗

BA1 ENIGMA BA1 (Stand-Alone benign) requires FAF > 0.1% in gnomAD non-founder populations. The grpmax FAF for this variant is 5.39e-05 (0.00539%) in gnomAD v2.1 and 2.154e-05 (0.00215%) in gnomAD v4.1, both well below the 0.1% threshold. The elevated Ashkenazi Jewish AF (0.589%) is attributable to a known founder effect and is excluded per ENIGMA's non-founder population stipulation. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 grpmax FAF = 5.39e-05 (0.00539%)
below BA1 0.1% threshold
gnomAD v4.1 grpmax FAF = 2.154e-05 (0.00215%)
Ashkenazi Jewish founder AF = 0.589% excluded per non-founder rule

Sources

gnomad_v2 ↗gnomad_v4 ↗

BP5 ENIGMA BP5 captures clinical-history LR against pathogenicity. The clinical-history LR from Li et al. 2020 is 31.79 (pathogenic direction). BP5 requires LR ≤0.48 for Supporting, which is not satisfied. The data strongly favor pathogenicity, not benignity. Details ▾Hide ▴

Evidence considered

Clinical-history LR = 31.79
far above BP5_Supporting threshold of ≤0.48
Data direction is pathogenic
not benign

Sources

vcep_pmid_31853058_brca2_clinical_history_lrPMID:31853058 ↗31853058

Not assessed · 6 · no assessment recorded

PS3 ENIGMA Table 9 (curated functional assay results) applies to missense and synonymous variants and contains no entry for this frameshift PTC variant. Frameshift null variants in BRCA2 are inherently loss-of-function; dedicated PS3 functional evidence is not required for classification. Details ▾Hide ▴

Evidence considered

ENIGMA Table 9 does not list this frameshift deletion
Frameshift PTC is inherently LOF in a tumor suppressor gene with established LOF mechanism

PS4 ENIGMA PS4 requires a formal case-control study with p-value ≤0.05, OR ≥4, and lower CI excluding 2.0. While the variant has been widely observed in affected individuals (149 probands in Li et al. 2020 clinical-history dataset; ClinVar reports 67 clinical laboratories classifying as Pathogenic), no published case-control study meeting ENIGMA PS4 specifications is available in the evidence packet. Details ▾Hide ▴

Evidence considered

ClinVar: 67 clinical laboratories classify as Pathogenic
expert panel (ENIGMA) review status
Li et al. 2020: 149 probands with this variant in clinical-history LR dataset
No formal case-control study with OR calculation available

Still missing

No published case-control study with OR ≥4 for this specific variant

Sources

clinvar ↗PMID:31853058 ↗31853058

PP1 ENIGMA PP1 requires quantitative co-segregation analysis with LR thresholds (Supporting ≥2.08, Moderate ≥4.3, Strong ≥18.7). Exploratory evidence suggests the variant may co-segregate with disease in families, but full-text verification of variant-specific segregation data was not possible (available full-text files were Sci-Hub boilerplate without paper content). No pedigree-level co-segregation LR is available in the evidence packet. Details ▾Hide ▴

Evidence considered

Exploratory search suggests possible segregation in families but full-text not verifiable
No quantitative co-segregation LR available

Still missing

No verified variant-specific co-segregation data with calculable LR
Full-text verification blocked by boilerplate-only full-text files

BS2 ENIGMA BS2 is applied in the absence of features of recessive Fanconi anemia (FA) phenotype in individuals carrying the variant. While most heterozygous carriers do not exhibit FA, BS2 requires systematic data on the absence of FA features in observed carriers. No such systematic dataset is available in the evidence packet. Details ▾Hide ▴

Evidence considered

Variant is observed heterozygously in population databases without FA phenotype data
No systematic BS2 point assignment data available

Still missing

No systematic FA phenotype absence data for carriers of this variant

BS3 ENIGMA BS3 applies when well-established functional studies show no damaging effect on protein function. ENIGMA Table 9 lists pre-assigned BS3 codes for missense/synonymous variants only. This frameshift PTC variant is predicted to cause complete loss of function via protein truncation and NMD; no functional evidence of a benign effect exists or is expected. Details ▾Hide ▴

Evidence considered

ENIGMA Table 9 does not list this frameshift deletion
Frameshift PTC predicted to ablate protein function
benign functional effect not expected

BS4 ENIGMA BS4 requires quantitative lack-of-segregation analysis (LR ≤0.48 for Supporting). No variant-specific non-segregation data is available in the evidence packet. The variant is a known pathogenic founder mutation; segregation data, if it exists, would more likely support pathogenicity. Details ▾Hide ▴

Evidence considered

No lack-of-segregation data available
Variant is classified as Pathogenic by ENIGMA expert panel

Still missing

No quantitative non-segregation LR data

Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/APS1 per ENIGMA applies to predicted missense substitutions with a previously classified pathogenic comparator acting via the same protein change, or to exonic/intronic variants with the same predicted splicing impact as a known pathogenic variant. This is a frameshift PTC variant and does not fall under either PS1 rule. Details ▾Hide ▴

No further detail was recorded.

PS2 VCEPPS2 is marked Not Applicable by the ENIGMA BRCA2 VCEP specification. Details ▾Hide ▴

No further detail was recorded.

PM1 VCEPPM1 is marked Not Applicable by the ENIGMA BRCA2 VCEP specification. Details ▾Hide ▴

No further detail was recorded.

PM4 VCEPPM4 is marked Not Applicable by the ENIGMA BRCA2 VCEP specification. Details ▾Hide ▴

No further detail was recorded.

PM6 VCEPPM6 is marked Not Applicable by the ENIGMA BRCA2 VCEP specification. Details ▾Hide ▴

No further detail was recorded.

PP2 VCEPPP2 is marked Not Applicable by the ENIGMA BRCA2 VCEP specification. Details ▾Hide ▴

No further detail was recorded.

PP3 N/AENIGMA PP3 applies to missense/in-frame variants inside clinically important functional domains with BayesDel ≥0.30, or to variants with predicted splicing impact (SpliceAI ≥0.2) for silent/missense/in-frame/intronic variants. This is a frameshift PTC variant with SpliceAI max delta score of 0.00; PP3 criteria are not applicable. Per ENIGMA, PP3 is not stacked on PVS1 for the same splice-effect evidence. Details ▾Hide ▴

Evidence considered

Frameshift PTC variant
not missense/in-frame/silent/intronic
SpliceAI max delta score = 0.00

Sources

spliceai ↗

BP1 N/AENIGMA BP1 applies to silent substitutions, missense variants, or in-frame insertions/deletions/delins variants outside clinically important functional domains with no splicing predicted. This is an out-of-frame frameshift deletion producing a PTC, not an in-frame variant, and is therefore not eligible for BP1. Details ▾Hide ▴

No further detail was recorded.

BP2 VCEPBP2 is marked Not Applicable by the ENIGMA BRCA2 VCEP specification. Details ▾Hide ▴

No further detail was recorded.

BP3 VCEPBP3 is marked Not Applicable by the ENIGMA BRCA2 VCEP specification. Details ▾Hide ▴

No further detail was recorded.

BP4 N/AENIGMA BP4 applies to missense/in-frame variants inside clinically important functional domains with no predicted impact (BayesDel ≤0.18 and SpliceAI ≤0.1), or to silent/intronic variants with no splicing predicted. This is a frameshift PTC variant, not a missense/in-frame/silent variant; BP4 is not applicable. Details ▾Hide ▴

No further detail was recorded.

BP6 VCEPBP6 is marked Not Applicable by the ENIGMA BRCA2 VCEP specification. Details ▾Hide ▴

No further detail was recorded.

BP7 N/AENIGMA BP7 applies to silent/intronic variants or to well-established functional mRNA studies showing no damaging effect on splicing. This is a frameshift PTC variant with SpliceAI max delta 0.00; BP7 does not apply. ENIGMA BP7 (RNA) is for intronic/silent/missense/in-frame variants with mRNA assay evidence, not for frameshift null variants. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 is not an active criterion under the ENIGMA BRCA2 VCEP specification. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: BRCA2
Transcript: NM_000059.4
Coding (HGVS c.): NM_000059.4:c.5946del
Protein (HGVS p.): NP_000050.3:p.(Ser1982ArgfsTer22)
GRCh38: chr13:32340300 GT>G
GRCh37: chr13:32914437 GT>G
ClinVar: 9325
COSMIC: COSV66447676

Gene diagram

Every interpreted variant in BRCA2, mapped onto the exon structure of NM_000059.4. Select a row to find it on the plot.

BRCA2NM_000059.4

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in BRCA2 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 225 / 1,613,878 alleles AF 0.000139 · 0 homozygotes · FAF 2.15e-05

gnomAD v2.1 78 / 282,088 alleles AF 0.000277 · 0 homozygotes · FAF 5.39e-05

gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD v4.1

AF 0.00014 · 225 / 1,613,878 alleles · 0 hom · FAF 2.2e-05

Ashkenazi Jewish158 / 29,596	0.0053
Remaining individuals31 / 62,478	0.0005
European (non-Finnish)35 / 1,179,918	3e-05
African/African American1 / 74,912	1.3e-05

0 alternate alleles recorded in 6 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian.

gnomAD v2.1

AF 0.00028 · 78 / 282,088 alleles · 0 hom · FAF 5.4e-05

Ashkenazi Jewish61 / 10,364	0.0059
Remaining individuals3 / 7,180	0.00042
European (non-Finnish)14 / 128,890	0.00011

0 alternate alleles recorded in 5 other groups: African/African American, Admixed American, East Asian, European (Finnish), South Asian.

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.000139416; MAF= 0.01394%, 225/1613878 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00533856; MAF= 0.53386%, 158/29596 alleles, homozygotes = 0); grpmax FAF= 2.154e-05.

gnomAD v2.1

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat -3 bp

0.000

SpliceAI acceptor gainat -8 bp

0.000

SpliceAI donor lossat +202 bp

0.000

SpliceAI donor gainat -445 bp

0.000

Pangolin splice lossmagnitude shown

-0.050

Pangolin splice gain

0.010

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

Frameshift PTC variant
not missense/in-frame/silent/intronic
SpliceAI max delta score = 0.00

Sources

spliceai ↗

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

9 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

Truncated BRCA2 is cytoplasmic: implications for cancer-linked mutations.

Spain BH et al. · 1999

No paper-specific finding is recorded.

PMID 10570174 ↗
BRCA2 is required for homology-directed repair of chromosomal breaks.

No paper-specific finding is recorded.

PMID 11239455 ↗
A new mutation of BRCA2 gene in an Italian healthy woman with familial breast cancer history.

No paper-specific finding is recorded.

PMID 20878484 ↗
BRCA1 and BRCA2: different roles in a common pathway of genome protection.

No paper-specific finding is recorded.

PMID 22193408 ↗
A comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast cancer.

No paper-specific finding is recorded.

PMID 24312913 ↗
De novo BRCA1 mutation in a patient with breast cancer and an inherited BRCA2 mutation.

Tesoriero A et al. · 1999

No paper-specific finding is recorded.

PMID 10417300 ↗
Shared genetic susceptibility to breast cancer, brain tumors, and Fanconi anemia.

Offit K et al. · 2003

No paper-specific finding is recorded.

PMID 14559878 ↗
The frequency of founder mutations in the BRCA1, BRCA2, and APC genes in Australian Ashkenazi Jews: implications for the generality of U.S. population data.

Bahar AY et al. · 2001

No paper-specific finding is recorded.

PMID 11466700 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

No paper-specific finding is recorded.

PMID 28492532 ↗

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

gnomAD v4.1 225 / 1,613,878 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗

ClinVar 67 Pathogenic · 1 pathogenic Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

OncoKB Captured OncoKB 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

gnomAD v2.1

ClinVar

This variant has been reported in ClinVar as Pathogenic (67 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 9325)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV66447676, n = 10 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.