BRCA1c.4689C>GPathogenic

Print report

Variant interpretation report

BRCA1 c.4689C>G, p.(Tyr1563Ter)

NM_007294.4:c.4689C>G NP_009225.1:p.(Tyr1563Ter) 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 BRCA1

No gene-level summary was recorded for this case.

Key facts

Condition: BRCA1-related cancer predisposition
Inheritance: Autosomal dominant
Evidence used: 1 very strong (pathogenic) · 2 strong (pathogenic) · 1 supporting (pathogenic)
Expert rules: ClinGen BRCA1 VCEP v1.2
Other laboratories (ClinVar): 39 Pathogenic · 1 Uncertain significance · 1 pathogenic
Pipeline record: 28 Jul 2026 · version 7.0.4

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): Nonsense variant NM_007294.4:c.4689C>G (p.Tyr1563Ter) in BRCA1 exon 15(16), a gene where loss-of-function is an established disease mechanism for hereditary breast and ovarian cancer. ENIGMA Table 4 assigns PVS1 at full strength for protein termination codon variants in exon 15(16). Nonsense-mediated decay is predicted as the premature termination codon is located well upstream of the last exon-exon junction and outside the NMD escape boundary annotated in the ENIGMA specification.
PM5 (strong): ENIGMA Table 4 assigns PM5_Strong (PTC) for protein termination codon variants in BRCA1 exon 15(16). This exon is not among the PM5_N/A exons (E21(22), E6(7), E7(8)). Supplementary Table ST1 confirms PM5_Strong with 15 total evidence points: functional assay PTC loss-of-function (4 points), functional assay missense loss-of-function (2 points), personal and family history LR (4 points), standardised incidence ratio (4 points), and CIMBA (1 point). Multiple proven pathogenic PTC variants have been observed in this exon.
PP4 (strong): Li et al. 2020 (PMID:31853058) clinical-history likelihood ratio for c.4689C>G is 159.82 (LOG(LR)=5.074, N=17 probands), exceeding the ENIGMA PP4_Strong threshold of LR ≥ 18.7. The variant's personal and family cancer history profile is highly consistent with that observed for known pathogenic BRCA1 variants.
PP5 (supporting): Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Pathogenic.

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 BRCA1 VCEP v1.2. 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: 0

Pathogenic criteria applied · 4

PVS1Very strong

PVS1 · very strong

Nonsense variant NM_007294.4:c.4689C>G (p.Tyr1563Ter) in BRCA1 exon 15(16), a gene where loss-of-function is an established disease mechanism for hereditary breast and ovarian cancer. ENIGMA Table 4 assigns PVS1 at full strength for protein termination codon variants in exon 15(16). Nonsense-mediated decay is predicted as the premature termination codon is located well upstream of the last exon-exon junction and outside the NMD escape boundary annotated in the ENIGMA specification.

PM5Strong

PM5 · strong

ENIGMA Table 4 assigns PM5_Strong (PTC) for protein termination codon variants in BRCA1 exon 15(16). This exon is not among the PM5_N/A exons (E21(22), E6(7), E7(8)). Supplementary Table ST1 confirms PM5_Strong with 15 total evidence points: functional assay PTC loss-of-function (4 points), functional assay missense loss-of-function (2 points), personal and family history LR (4 points), standardised incidence ratio (4 points), and CIMBA (1 point). Multiple proven pathogenic PTC variants have been observed in this exon.

PP4Strong

PP4 · strong

Li et al. 2020 (PMID:31853058) clinical-history likelihood ratio for c.4689C>G is 159.82 (LOG(LR)=5.074, N=17 probands), exceeding the ENIGMA PP4_Strong threshold of LR ≥ 18.7. The variant's personal and family cancer history profile is highly consistent with that observed for known pathogenic BRCA1 variants.

PP5Supporting

PP5 · supporting

Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Pathogenic.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

ENIGMA BRCA1/BRCA2 VCEP v1.2 Table 3: ≥1 Very Strong + ≥1 Strong → Pathogenic. PVS1 (Very Strong) + PM5_Strong (Strong) + PP4_Strong (Strong) satisfy this rule. No benign criteria are met. Point-system corroboration: +17 points (≥10 threshold for 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

5 / 1,614,030 alleles

gnomAD v4.1: 5 / 1,614,030 alleles. Recorded AF 3.09784e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.98877e-06; MAF= 0.00040%, 1/250704 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.83798e-06; MAF= 0.00088%, 1/113148 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

No listed criterion applied

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

SpliceAI score

0.030 maximum delta

Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗

ClinVar submissions

41 reported laboratory submissions

39 Pathogenic · 1 Uncertain significance · 1 pathogenic. ClinVar API review status: reviewed by expert panel.

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

No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

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 BRCA1 VCEP v1.2, with the data and sources behind each one.

26 criteria with recorded statuses: 4 met · 6 not met · 4 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

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

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_007294.4:c.4689C>G (p.Tyr1563Ter) is a nonsense variant in BRCA1 exon 15(16) that creates a premature termination codon.

PVS1 is met at Very Strong strength: loss-of-function is an established disease mechanism for BRCA1, and the ENIGMA Table 4 PVS1 decision framework assigns full-strength PVS1 to protein termination codon variants in exon 15(16). Nonsense-mediated decay is predicted as the PTC at codon 1563 is upstream of the annotated NMD escape boundary.

PM5_Strong (PTC) is met: ENIGMA Table 4 assigns PM5_Strong for PTC variants in exon 15(16), supported by 15 total evidence points in Supplementary Table ST1 spanning functional assay data, clinical history, and population-level evidence.

PP4_Strong is met: the clinical-history likelihood ratio from Li et al. 2020 (PMID:31853058) is 159.82 (17 probands), greatly exceeding the ENIGMA PP4_Strong threshold of LR ≥ 18.7. The variant's personal and family cancer history is highly consistent with known pathogenic BRCA1 variants.

PM2 is not met: the variant is observed at extremely low frequency in gnomAD (v2.1: 1/250,704; v4.1: 5/1,614,030). Under ENIGMA, a single observation in an outbred population is not considered informative for PM2 assignment.

PS3 is not met: no variant-specific functional assay data exist for c.4689C>G in the ENIGMA Table 9 curated functional assay results or in the reviewed literature.

No benign criteria are met. The population frequencies are far below BS1 and BA1 thresholds, no functional data support BS3, and the clinical history LR is in the pathogenic direction.

Combined classification: PVS1 (Very Strong) + PM5_Strong (Strong) + PP4_Strong (Strong) meets ENIGMA Table 3 pathogenic combination rule (≥1 Very Strong + ≥1 Strong).

Met · 4

PVS1 Very strongNonsense variant NM_007294.4:c.4689C>G (p.Tyr1563Ter) in BRCA1 exon 15(16), a gene where loss-of-function is an established disease mechanism for hereditary breast and ovarian cancer. ENIGMA Table 4 assigns PVS1 at full strength for protein termination codon variants in exon 15(16). Nonsense-mediated decay is predicted as the premature termination codon is located well upstream of the last exon-exon junction and outside the NMD escape boundary annotated in the ENIGMA specification. Details ▾Hide ▴

Evidence considered

Nonsense variant creating premature termination codon at p.Tyr1563Ter in BRCA1 exon 15(16)
ENIGMA Table 4 assigns PVS1 (full strength) for PTC variants in exon 15(16)
BRCA1 loss-of-function is an established germline disease mechanism per ClinGen ENIGMA VCEP v1.2
NMD predicted: PTC at codon 1563 is upstream of exon 23(24) NMD escape boundary (p.1855)

Sources

vcep_specifications_table4_v1_2_2024_11_18cspec ↗

PM5 StrongENIGMA Table 4 assigns PM5_Strong (PTC) for protein termination codon variants in BRCA1 exon 15(16). This exon is not among the PM5_N/A exons (E21(22), E6(7), E7(8)). Supplementary Table ST1 confirms PM5_Strong with 15 total evidence points: functional assay PTC loss-of-function (4 points), functional assay missense loss-of-function (2 points), personal and family history LR (4 points), standardised incidence ratio (4 points), and CIMBA (1 point). Multiple proven pathogenic PTC variants have been observed in this exon. Details ▾Hide ▴

Evidence considered

ENIGMA Table 4: PM5_Strong (PTC) assigned to exon 15(16)
ENIGMA ST1: 15 total evidence points across 5 categories support PM5_Strong for exon 15(16)
4 functional assay studies confirm PTC loss-of-function in exon 15(16)
Exon 15(16) is not in the PM5_N/A exclusion list (E21
E6
E7)

Sources

vcep_specifications_table4_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18cspec ↗

PP4 StrongLi et al. 2020 (PMID:31853058) clinical-history likelihood ratio for c.4689C>G is 159.82 (LOG(LR)=5.074, N=17 probands), exceeding the ENIGMA PP4_Strong threshold of LR ≥ 18.7. The variant's personal and family cancer history profile is highly consistent with that observed for known pathogenic BRCA1 variants. Details ▾Hide ▴

Evidence considered

Clinical-history LR = 159.82 (Li et al. 2020
PMID:31853058)
N = 17 probands
Exceeds PP4_Strong threshold of LR ≥ 18.7
LOG(LR) = 5.074 in BRCA1 clinical_history_LR table

Sources

PMID:31853058 ↗vcep_pmid_31853058_brca1_clinical_history_lrcspec ↗

PP5 SupportingExpert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Pathogenic. Details ▾Hide ▴

Evidence considered

ClinVar expert panel classification

Sources

cspec ↗clinvar ↗

Not met · 6 · evaluated, threshold not reached

PS3 ENIGMA Table 9 contains no pre-assigned PS3 code for c.4689C>G, and no variant-specific functional data were identified in the literature. Under the ENIGMA framework, functional evidence for protein termination codon variants is captured by PVS1 and PM5_PTC rather than PS3, which is applied primarily to missense variants with calibrated functional assay results. Details ▾Hide ▴

Evidence considered

c.4689C>G not listed in ENIGMA Table 9 curated functional assay results
c.4689C>G not present in Supplementary Table ST4 functional assay dataset
No variant-specific functional publications identified in full-text or abstract review

Sources

vcep_specifications_table9_v1_2_2024_11_18

PM2 ENIGMA PM2_Supporting requires absence from gnomAD controls in outbred populations. c.4689C>G is present in gnomAD v2.1 (1/250,704 alleles; AF=3.99e-6; European non-Finnish) and gnomAD v4.1 (5/1,614,030 alleles; AF=3.10e-6; European non-Finnish). ENIGMA specifically states that observation of a variant only once in a gnomAD outbred population is not informative; PM2 is not met. Details ▾Hide ▴

Evidence considered

Present in gnomAD v2.1: 1/250
704 alleles (AF=3.99e-6)
European non-Finnish
Present in gnomAD v4.1: 5/1
614
030 alleles (AF=3.10e-6)
ENIGMA PM2 instructions: single observation in outbred population is not informative

Sources

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

BA1 ENIGMA BA1 requires filter allele frequency (FAF) > 0.1% in gnomAD v2.1 or v3.1 non-founder populations. The maximum allele frequency for c.4689C>G is 4.24e-6 (0.00042%) in gnomAD v4.1 European non-Finnish, far below the BA1 threshold. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 max AF: 4.24e-6 (European non-Finnish)
gnomAD v2.1 max AF: 8.84e-6 (European non-Finnish)
ENIGMA BA1 threshold: FAF > 0.1%

Sources

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

BS1 ENIGMA BS1_Supporting requires FAF > 0.002% in gnomAD non-founder populations; BS1_Strong requires FAF > 0.01%. The maximum allele frequency for c.4689C>G is 4.24e-6 (0.00042%), below both the Supporting and Strong thresholds. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 max AF: 4.24e-6 (0.00042%)
ENIGMA BS1_Supporting threshold: FAF > 0.002%
ENIGMA BS1_Strong threshold: FAF > 0.01%

Sources

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

BS3 ENIGMA Table 9 contains no pre-assigned BS3 code for c.4689C>G. No well-established functional studies demonstrating no damaging effect on protein function were identified for this variant in the literature. Details ▾Hide ▴

Evidence considered

c.4689C>G not listed in ENIGMA Table 9 curated functional assay results
No variant-specific functional data showing no damaging effect identified

Sources

vcep_specifications_table9_v1_2_2024_11_18

BP5 The Li et al. 2020 clinical-history LR for c.4689C>G is 159.82 in the pathogenic direction. ENIGMA BP5 requires LR ≤ 0.48 (Supporting) or lower; the observed LR is far above the benign thresholds. Details ▾Hide ▴

Evidence considered

Clinical-history LR = 159.82 (pathogenic direction)
BP5_Supporting threshold: LR ≤ 0.48
not met

Sources

PMID:31853058 ↗vcep_pmid_31853058_brca1_clinical_history_lr

Not assessed · 4 · no assessment recorded

PS4 No case-control study satisfying ENIGMA PS4 requirements (p ≤ 0.05, OR ≥ 4, lower confidence interval excludes 2.0, ethnicity- and country-matched controls) was identified for c.4689C>G in the case materials. Details ▾Hide ▴

Still missing

No variant-specific case-control study available

PP1 No quantitative co-segregation analysis data meeting ENIGMA PP1 thresholds (LR ≥ 2.08 by Bayes score) was available for c.4689C>G in the case materials. Details ▾Hide ▴

Still missing

No co-segregation data available for this variant

BS2 No individual-level co-occurrence data with Fanconi Anemia phenotype or healthy adult observation meeting ENIGMA Table 8 criteria was available for c.4689C>G in the case materials. Details ▾Hide ▴

Still missing

No proband-level co-occurrence data with Fanconi Anemia phenotype assessment

BS4 No quantitative co-segregation analysis data showing lack of segregation meeting ENIGMA BS4 thresholds was available for c.4689C>G in the case materials. Details ▾Hide ▴

Still missing

No co-segregation data available

Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/APS1 under ENIGMA v1.2 applies to predicted missense substitutions or exonic/intronic variants with same predicted splicing impact as a previously classified pathogenic variant. This is a nonsense variant; PS1 does not apply to protein termination codon variants in this framework. Details ▾Hide ▴

No further detail was recorded.

PS2 VCEPENIGMA v1.2 declares PS2 Not Applicable: BRCA1/2-related cancers occur relatively commonly; no information is available to calibrate the predictive capacity of de novo occurrences. Details ▾Hide ▴

Sources

cspec ↗

PM1 VCEPENIGMA v1.2 declares PM1 Not Applicable; mutational hotspot and critical functional domain information is considered through the bioinformatic analysis codes (PP3/BP4) and the domain-specific framework rules in this VCEP. Details ▾Hide ▴

Sources

cspec ↗

PM6 VCEPENIGMA v1.2 declares PM6 Not Applicable: BRCA1/2-related cancers occur relatively commonly; no information to calibrate the predictive capacity of de novo occurrences. Details ▾Hide ▴

Sources

cspec ↗

PP2 VCEPENIGMA v1.2 declares PP2 Not Applicable. Details ▾Hide ▴

Sources

cspec ↗

PP3 N/APP3 under ENIGMA v1.2 applies to (a) missense or in-frame variants within a clinically important functional domain with BayesDel no-AF score ≥ 0.28, or (b) variants with SpliceAI ≥ 0.2 predicting altered splicing for silent/missense/in-frame/intronic variants. This is a nonsense variant with SpliceAI max delta 0.03 showing no predicted splicing impact; PP3 does not apply. Details ▾Hide ▴

Evidence considered

SpliceAI max delta score 0.03: no predicted splicing impact
PP3 under ENIGMA does not apply to nonsense variants

Sources

spliceai ↗cspec ↗

BP1 N/AENIGMA BP1_Strong applies only to silent substitution, missense, or in-frame insertion/deletion/delins variants outside a clinically important functional domain with SpliceAI ≤ 0.1. This is a nonsense variant; BP1 does not apply. Details ▾Hide ▴

Sources

cspec ↗

BP2 VCEPENIGMA v1.2 declares BP2 Not Applicable; applied only in the context of BS2. Details ▾Hide ▴

Sources

cspec ↗

BP4 N/AENIGMA BP4 applies only to missense/in-frame variants within clinically important functional domains with BayesDel ≤ 0.15 and SpliceAI ≤ 0.1, or to silent/intronic variants with SpliceAI ≤ 0.1. This is a nonsense variant; BP4 does not apply. Details ▾Hide ▴

Sources

cspec ↗

BP6 VCEPENIGMA v1.2 declares BP6 Not Applicable for this VCEP, per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴

Sources

cspec ↗

BP7 N/AENIGMA BP7 applies to silent/intronic variants with mRNA assay data showing no splicing effect, or to missense/in-frame variants outside clinically important functional domains with well-established mRNA splicing assays. This is a nonsense variant; BP7 does not apply. Details ▾Hide ▴

Sources

cspec ↗

PS5 N/APS5 under generic ACMG/AMP applies to novel missense changes at an amino acid residue where a different pathogenic missense change has been seen. This is a nonsense variant (p.Tyr1563Ter); PS5 does not apply. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: BRCA1
Transcript: NM_007294.4
Coding (HGVS c.): NM_007294.4:c.4689C>G
Protein (HGVS p.): NP_009225.1:p.(Tyr1563Ter)
GRCh38: chr17:43071225 G>C
GRCh37: chr17:41223242 G>C
ClinVar: 2108449, 1054980, 868382, 865723, 865027, 803401, 37607, 633099, 55252, 55229

Gene diagram

Every interpreted variant in BRCA1, mapped onto the exon structure of NM_007294.4. Select a row to find it on the plot.

BRCA1NM_007294.4

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 BRCA1 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 5 / 1,614,030 alleles AF 3.1e-06 · 0 homozygotes · FAF 1.24e-06

gnomAD v2.1 1 / 250,704 alleles AF 3.99e-06 · 0 homozygotes

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 3.1e-06 · 5 / 1,614,030 alleles · 0 hom · FAF 1.2e-06

European (non-Finnish)5 / 1,180,002

4.2e-06

0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 4e-06 · 1 / 250,704 alleles · 0 hom

European (non-Finnish)1 / 113,148

8.8e-06

0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 3.09784e-06; MAF= 0.00031%, 5/1614030 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.23728e-06; MAF= 0.00042%, 5/1180002 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.

gnomAD v2.1

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +13 bp

0.000

SpliceAI acceptor gainat +77 bp

0.030

SpliceAI donor lossat -362 bp

0.000

SpliceAI donor gainat -204 bp

0.000

Pangolin splice lossmagnitude shown

-0.030

Pangolin splice gain

0.010

Other predictors

REVEL: Not available
BayesDel: 0.280

How the predictions were used

Evidence considered

SpliceAI max delta score 0.03: no predicted splicing impact
PP3 under ENIGMA does not apply to nonsense variants

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). BayesDel score = 0.280476.

8 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

Tumorigenesis in mice carrying a truncating Brca1 mutation.

Describes a genetically engineered mouse model carrying a Brca1 truncation mutation (Brca1tr) that eliminates the C-terminal half of the protein. The study reports tumorigenesis in homozygous mutants including lymphomas, sarcomas, and mammary carcinomas. NM_007294.4:c.4689C>G was not identified in this paper.
Does not name this variant
PMID 11358863 ↗
The cancer connection: BRCA1 and BRCA2 tumor suppression in mice and humans.

No paper-specific finding is recorded.

PMID 12483515 ↗
Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation.

Reviews the roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity, and cellular response to ionizing radiation. NM_007294.4:c.4689C>G was not identified in this paper.
Does not name this variant
PMID 12947386 ↗
BRCA1 16 years later: risk-associated BRCA1 mutations and their functional implications.

No paper-specific finding is recorded.

PMID 20608970 ↗
Caspase-dependent BRCA1 cleavage facilitates chemotherapy-induced apoptosis.

No paper-specific finding is recorded.

PMID 18071904 ↗
Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.

Borg A et al. · 2010

WECARE study characterizing BRCA1 and BRCA2 deleterious mutations and VUS in a population-based sample of young women with contralateral or unilateral breast cancer. Identified 470 unique sequence variants. NM_007294.4:c.4689C>G was not identified in this paper.
Does not name this variant
PMID 20104584 ↗
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.

ACMG/AMP standards and guidelines for sequence variant interpretation. Provides the generic framework for variant classification criteria. NM_007294.4:c.4689C>G was not identified in this paper.
Does not name this variant
PMID 25741868 ↗
A high incidence of BRCA1 mutations in 20 breast-ovarian cancer families.

Serova O et al. · 1996

No paper-specific finding is recorded.

PMID 8554067 ↗

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

gnomAD v4.1 5 / 1,614,030 recorded alleles Open source ↗

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

SpliceAI Lookup Recorded maximum delta 0.030 Open source ↗

ClinVar 39 Pathogenic · 1 Uncertain significance · 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

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Pathogenic (39 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as pathogenic (1 clinical laboratory) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 37607)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). BayesDel score = 0.280476.

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 not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.