chr17-43063361-G-A

Variant names:

• chr17-43063361-G-A
• rs80357104
• NM_007294.4:c.5165C>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 PM1 PM2 PM5 PP3_Moderate PP5

The NM_007294.4(BRCA1):​c.5165C>T​(p.Ser1722Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000076852: Experimental studies have shown that this missense change affects BRCA1 function (PMID:12496477, 20516115)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1722A) has been classified as Uncertain significance. The gene BRCA1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:19 U:2
• Conservation: PhyloP100: 3.43
• Publications: 22 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

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

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000076852: Experimental studies have shown that this missense change affects BRCA1 function (PMID: 12496477, 20516115).; SCV000699216: "decreased structural stability, impaired phosphopeptide binding and transcriptional activity (Lee_2010); and in a recent high throughput genome editing assay the variant resulted in a decreased (intermediate) function when testing it in a haploid human cell line whose survival is dependent on intact BRCA1 function (Findlay_2018)."; SCV004847823: "In vitro functional studies support an impact on protein function (Lee 2010, Carvalho 2002)."; SCV005045702: Functional assays showed a strong deleterious effect [PMID 20516115].; SCV000839899: Functional assays showed a strong deleterious effect [PMID 20516115].; SCV004817580: Multiple functional studies have consistently shown that this variant results in the loss of transcription activation function of BRCA1 protein (PMID: 12496477, 15172985, 20516115, 30765603).; SCV000273727: Based on multiple structural and functional analyses, this alteration was shown to significantly alter protease sensitivity, peptide binding activity, peptide binding specificity, and transcriptional activity of the mutant protein compared to wild type (Mirkovic N et al. Cancer Res. 2004 Jun;64:3790-7; Lee MS et al. Cancer Res. 2010 Jun;70:4880-90).; SCV000683267: Multiple functional studies have consistently shown that this variant results in the loss of transcription activation function of BRCA1 protein (PMID: 12496477, 15172985, 20516115, 30765603).; SCV000293277: Published functional studies demonstrate a damaging effect with respect to protein folding, phosphopeptide binding activity and specificity, transcriptional activity, homology-directed repair, and cell viability (PMID: 12496477, 20516115, 30209399, 30765603, 35665744); SCV000296373: "In addition, functional studies describe the p.Ser1722Phe variant as having a deleterious effect on BRCA1 protein function (PMID: 12496477 (2002), 15172985 (2004), 20516115 (2010))."; SCV006325686: Functional studies have indicated that this variant results in the loss of transcription activation function of BRCA1 protein (PMID: 12496477, 15172985, 20516115, 30765603).; SCV000591589: "The BRCA1 p.Ser1722Ph variant falls within the BRCA1 C-terminus (BRCT) domain and was shown, in a yeast based transcription activation assay, to be temperature sensitive whereby activity was abolished at 37oC, and therefore likely represents a cancer-associated variant (Carvalho 2002)."
• PM1: In a hotspot region, there are 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 16 benign, 77 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 chr17-43063362-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 125791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.848
• PP5: Variant 17-43063361-G-A is Pathogenic according to our data. Variant chr17-43063361-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 55441.

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.5165C>T	p.Ser1722Phe	missense	Exon 18 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.5231C>T	p.Ser1744Phe	missense	Exon 19 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.5231C>T	p.Ser1744Phe	missense	Exon 19 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.5165C>T	p.Ser1722Phe	missense	Exon 18 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.5228C>T	p.Ser1743Phe	missense	Exon 19 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.5165C>T	p.Ser1722Phe	missense	Exon 18 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459212 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726170

African (AFR) AF: 0.00 AC: 0 AN: 33418

American (AMR) AF: 0.0000224 AC: 1 AN: 44712

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109798

Other (OTH) AF: 0.00 AC: 0 AN: 60318

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
7	1	-	Breast-ovarian cancer, familial, susceptibility to, 1 (8)
4	-	-	Hereditary breast ovarian cancer syndrome (4)
4	-	-	not provided (4)
2	1	-	Hereditary cancer-predisposing syndrome (3)
1	-	-	Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S (1)
1	-	-	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		3.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.87
MVP		0.89
MPC		0.47
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.87
gMVP		0.87
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs80357104; hg19: chr17-41215378; COSMIC: COSV58794522; COSMIC: COSV58794522;