rs45553935

Variant names:

• chr17-43057122-A-C
• rs45553935
• NM_007294.4:c.5207T>G
• BRCA1 p.Val1736Gly

Your query was ambiguous. Multiple possible variants found:

• chr17-43057122-A-C
• chr17-43057122-A-G
• chr17-43057122-A-T

Germline classificationCancer classification (beta)

Variant summary

Our verdict is

Pathogenic

+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

. The variant received 14 ACMG points: 14P and 0B. PS3PM1PM2PM5PP3_ModeratePP5_Moderate

The NM_007294.4(BRCA1):c.5207T>G (p.Val1736Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000699221: A functional study demonstrated the variant to decrease protein stability, phosphopeptide binding activity, phosphopeptide binding specificity and transcriptional activity of BRCA1 (Lee_2010)." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.V1736F: Likely_pathogenic (ClinVar VariationId 867843, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.V1736D: unknown significance (ClinVar VariationId 867844); p.V1736I: unknown significance (ClinVar VariationId 867518); p.V1736L: unknown significance (ClinVar VariationId 867842); p.V1736= (synonymous): unknown significance (ClinVar VariationId 867847); p.V1736= (synonymous): unknown significance (ClinVar VariationId 867846); p.V1736= (synonymous): unknown significance (ClinVar VariationId 867845) This exact variant is established as oncogenic in: CGI (Cancer Genome Interpreter).

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1 B:1
• Conservation: PhyloP100: 5.55
• Publications: 63 publications found

Genes affected

BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]

BRCA1 Gene-Disease associations (from GenCC):

• BRCA1-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• breast-ovarian cancer, familial, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• Fanconi anemia, complementation group S

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen
• pancreatic cancer, susceptibility to, 4

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Specifications for BRCA1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: Well-established functional study supports damaging effect (PS3); SCV000699221: A functional study demonstrated the variant to decrease protein stability, phosphopeptide binding activity, phosphopeptide binding specificity and transcriptional activity of BRCA1 (Lee_2010).; SCV001185640: A transcription activation assay found that this variant had <80% activity relative to wildtype and was, thus, considered deleterious (Fernandes VC et al. J. Biol. Chem., 2019 04;294:5980-5992). Another functional study found this alteration to be severely defective in all assays (Lee MS et al. Cancer Res., 2010 Jun;70:4880-90).; SCV001343891: Functional studies have shown that this variant impacts BRCA1 function in transcription activation and in a haploid cell proliferation assay (PMID: 20516115, 30209399).
• PM1: Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 20 pathogenic, 9 benign (OR vs. background: 10.8).
• PM2: Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.000118 by highest known P/LP ClinVar AF 0.000118) — PM2 moderate.
• PM5: Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.V1736F: Likely_pathogenic (ClinVar VariationId 867843, 2 stars); Other variants at the same amino acid residue (not pathogenic): p.V1736D: unknown significance (ClinVar VariationId 867844); p.V1736I: unknown significance (ClinVar VariationId 867518); p.V1736L: unknown significance (ClinVar VariationId 867842); p.V1736= (synonymous): unknown significance (ClinVar VariationId 867847); p.V1736= (synonymous): unknown significance (ClinVar VariationId 867846); p.V1736= (synonymous): unknown significance (ClinVar VariationId 867845)
• PP3: Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
• PP5: ClinVar 2-star pathogenic with significant benign submissions — moderate (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s), conflicting benign submissions present (P/LP: 4, B/LB: 1).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007294.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	NM_007294.4	MANE Select	c.5207T>G	p.Val1736Gly	missense	Exon 19 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.5273T>G	p.Val1758Gly	missense	Exon 20 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.5273T>G	p.Val1758Gly	missense	Exon 20 of 24	NP_001394511.1	A0A2R8Y7V5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.5207T>G	p.Val1736Gly	missense	Exon 19 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.5270T>G	p.Val1757Gly	missense	Exon 20 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.5207T>G	p.Val1736Gly	missense	Exon 19 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Hereditary cancer-predisposing syndrome (3)
-	1	-	Breast-ovarian cancer, familial, susceptibility to, 1 (1)
1	-	-	Hereditary breast ovarian cancer syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		5.6
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.83
gMVP		0.93
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs45553935;

hg19: chr17-41209139;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar