chr17-43063882-C-T

Variant names:

• chr17-43063882-C-T
• rs45444999
• NM_007294.4:c.5144G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM1 PM2 PM5 PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5144G>A​(p.Ser1715Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,404 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV002577234: Published functional studies demonstrate a damaging effect: impaired transciptional activity, structural stability, binding activity and specificity, protease sensitivity, cell survival, and homology-directed repair activity (Vallon-Christersson 2001, Lee 2010, Woods 2016, Findlay 2018, Fernandes 2019, Petitalot 2019, Lyra 2021).; SCV001185514: Numerous functional studies have shown that this variant is functionally defective including in homology directed repair, haploid cell survival, yeast growth retardation, transcriptional activation assays, binding activity and specificity, protease sensitivity, and overall stability (Vallon-Christersson J et al. Hum. Mol. Genet., 2001 Feb;10:353-60; Karchin R et al. PLoS Comput. Biol., 2007 Feb;3:e26; Lee MS et al. Cancer Res., 2010 Jun;70:4880-90; Rowling PJ et al. J. Biol. Chem., 2010 Jun;285:20080-7; Iversen ES et al. Cancer Epidemiol. Biomarkers Prev., 2011 Jun;20:1078-88; Findlay GM et al. Nature, 2018 10;562:217-222).; SCV001343897: Functional studies have reported that this variant impacts BRCA1 function in a haploid cell proliferation assay, transcription activation assays, homology-directed DNA repair assay, a nuclear localization assay, and other ancillary assays (PMID:11157798, 20516115, 29884841, 30209399, 30257991).; SCV005901917: It has been reported by three calibrated studies to affect protein function similar to pathogenic control variants (PMIDs: 30209399, 30257991, 30765603) (PS3 met).; SCV002139227: Experimental studies have shown that this missense change affects BRCA1 function (PMID:11157798, 20516115, 28781887, 30209399, 30765603).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1715T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:8 U:2
• Conservation: PhyloP100: 4.86
• Publications: 28 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Fanconi anemia, complementation group S

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

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002577234: Published functional studies demonstrate a damaging effect: impaired transciptional activity, structural stability, binding activity and specificity, protease sensitivity, cell survival, and homology-directed repair activity (Vallon-Christersson 2001, Lee 2010, Woods 2016, Findlay 2018, Fernandes 2019, Petitalot 2019, Lyra 2021).; SCV001185514: Numerous functional studies have shown that this variant is functionally defective including in homology directed repair, haploid cell survival, yeast growth retardation, transcriptional activation assays, binding activity and specificity, protease sensitivity, and overall stability (Vallon-Christersson J et al. Hum. Mol. Genet., 2001 Feb;10:353-60; Karchin R et al. PLoS Comput. Biol., 2007 Feb;3:e26; Lee MS et al. Cancer Res., 2010 Jun;70:4880-90; Rowling PJ et al. J. Biol. Chem., 2010 Jun;285:20080-7; Iversen ES et al. Cancer Epidemiol. Biomarkers Prev., 2011 Jun;20:1078-88; Findlay GM et al. Nature, 2018 10;562:217-222).; SCV001343897: Functional studies have reported that this variant impacts BRCA1 function in a haploid cell proliferation assay, transcription activation assays, homology-directed DNA repair assay, a nuclear localization assay, and other ancillary assays (PMID: 11157798, 20516115, 29884841, 30209399, 30257991).; SCV005901917: It has been reported by three calibrated studies to affect protein function similar to pathogenic control variants (PMIDs: 30209399, 30257991, 30765603) (PS3 met).; SCV002139227: Experimental studies have shown that this missense change affects BRCA1 function (PMID: 11157798, 20516115, 28781887, 30209399, 30765603).
• PM1: In a hotspot region, there are 22 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 12 benign, 68 uncertain in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43063883-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 55415.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP5: Variant 17-43063882-C-T is Pathogenic according to our data. Variant chr17-43063882-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 55416.Status of the report is reviewed_by_expert_panel, 3 stars.

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.5144G>A	p.Ser1715Asn	missense	Exon 17 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.5210G>A	p.Ser1737Asn	missense	Exon 18 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.5210G>A	p.Ser1737Asn	missense	Exon 18 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.5144G>A	p.Ser1715Asn	missense	Exon 17 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.5207G>A	p.Ser1736Asn	missense	Exon 18 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.5144G>A	p.Ser1715Asn	missense	Exon 17 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460404 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726612

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110700

Other (OTH) AF: 0.00 AC: 0 AN: 60334

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	1	-	Breast-ovarian cancer, familial, susceptibility to, 1 (3)
3	-	-	Hereditary cancer-predisposing syndrome (3)
2	1	-	not provided (3)
1	-	-	Hereditary breast ovarian cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	1.8	L
PhyloP100		4.9
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.30
Sift	Benign	0.059	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.43	B
Vest4		0.81
MVP		0.93
MPC		0.33
ClinPred		0.89	D
GERP RS		6.0
Varity_R		0.83
gMVP		0.83
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		0.0
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs45444999; hg19: chr17-41215899; COSMIC: COSV107367492;