rs80357104

Positions:

• chr17-43063361-G-A
• chr17-43063361-G-C
• chr17-43063361-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1722A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18 U:1 O:1
• Conservation: PhyloP100: 3.43

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 17 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 id 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 [Likely_pathogenic]. Clinvar id is 55441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43063361-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5165C>T	p.Ser1722Phe	missense_variant	18/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5165C>T	p.Ser1722Phe	missense_variant	18/23	1	NM_007294.4	P4

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:7 Uncertain:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	May 25, 2017	The c.5165C>T (p.Ser1722Phe) variant in the BRCA1 gene has been reported in two patients in the Breast Cancer Information Core database (accession number 10462 and 10461). The variant has also been reported in additional patients by clinical laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/55441). Functional assays showed a strong deleterious effect [PMID 20516115]. This variant was not observed in the ExAC database. Serine at amino acid position 1722 of the BRCA1 protein is conserved in mammals. Although not validated for clinical use, computer-based algorithms SIFT and Polyphen2 predict this p.Ser1722Phe change to be deleterious. This variant thus classified as likely pathogenic. -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Feb 20, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Apr 10, 2023	This missense variant replaces serine with phenylalanine at codon 1722 in the BRCT1 domain of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). 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). This variant has been reported in at least six individuals affected with hereditary breast and/or ovarian cancer (PMID: 22476429, 33526602; Color internal data). An external laboratory has concluded this variant to be Pathogenic based on analysis of personal and family history of 44 probands (PMID: 25085752). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 19, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Aug 17, 2012	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 11, 2021	Variant summary: BRCA1 c.5165C>T (p.Ser1722Phe) results in a non-conservative amino acid change located in the first BRCT domain (IPR001357) that binds ATM-phosphorylated proteins (e.g. abraxas, CtIP and BRIP1; see PMID 22193408). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251036 control chromosomes (gnomAD). c.5165C>T has been reported in the literature in individuals with personal and/or family history of breast- and ovarian cancer (Judkins_2005, Lu_2012, Chan_2018, Lynce_2020). Publications also reported experimental evidence, demonstrating 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). Ten other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=2) or likely pathogenic (n=8). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	May 12, 2021	The c.5165C>T (p.Ser1722Phe) variant in the BRCA1 gene has been reported in two patients in the Breast Cancer Information Core database (accession number 10462 and 10461). The variant has also been reported in additional patients by clinical laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/55441). Functional assays showed a strong deleterious effect [PMID 20516115]. This variant was not observed in the ExAC database. Serine at amino acid position 1722 of the BRCA1 protein is conserved in mammals. Although not validated for clinical use, computer-based algorithms SIFT and Polyphen2 predict this p.Ser1722Phe change to be deleterious. This variant thus classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 23, 2020	The p.Ser1722Phe variant in BRCA1 has been reported in at least 3 individual with breast cancer (Lu 2012, Breast Information Core (BIC) database). In addition, this variant has also been reported in ClinVar (Variation ID 55441) and was absent from large population databases. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies support an impact on protein function (Lee 2010, Carvalho 2002 ). In addition, this variant lies within a binding motif in BRCA1. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Hereditary breast and ovarian cancer. PM1, PM2, PP3, PS3_Supporting, PS4_Supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 1722 of the BRCA1 protein (p.Ser1722Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 22476429, 28888541, 30093976, 35264596). ClinVar contains an entry for this variant (Variation ID: 55441). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BRCA1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 12496477, 20516115). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 29, 2021	This variant has been reported in individuals and families affected with breast/ovarian cancer (PMID: 16267036 (2005), 22476429 (2012), 29446198 (2018), 30093976 (2018), 30264118 (2018), 31481248 (2019), 33010199 (2020)) and described as pathogenic based on a multifactorial likelihood algorithm in the published literature (PMID: 25085752 (2014)). 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)). Based on the available information, this variant is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2023	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 (Carvhalo et al., 2002; Lee et al., 2010; Findlay et al., 2018; Fernandes et al., 2019; Iversen et al., 2022); Observed in individuals with BRCA1-related cancers (Lu et al., 2012; Chan et al., 2018; Mersch et al., 2018; Ow et al., 2019; Guindalini et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 5284C>T; This variant is associated with the following publications: (PMID: 15172985, 30209399, 16267036, 20516115, 25085752, 12496477, 17305420, 22476429, 28781887, 15385441, 29446198, 23704879, 30264118, 30093976, 30765603, 31447099, 33087888, 30875412, 30787465, 33526602, 25348405, 32377563, 35665744, 29884841, 35264596, 33206196, 33010199) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 08, 2022	This missense variant replaces serine with phenylalanine at codon 1722 in the BRCT1 domain of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). 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). This variant has been reported in at least six individuals affected with hereditary breast and/or ovarian cancer (PMID: 22476429, 33526602; Color internal data). An external laboratory has concluded this variant to be Pathogenic based on analysis of personal and family history of 44 probands (PMID: 25085752). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 27, 2021	The p.S1722F pathogenic mutation (also known as c.5165C>T), located in coding exon 17 of the BRCA1 gene, results from a C to T substitution at nucleotide position 5165. The serine at codon 1722 is replaced by phenylalanine, an amino acid with highly dissimilar properties. 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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 14, 2021

- -

Malignant tumor of breast Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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). Lee et al (2010) used 3 biochemical and cell-based transcriptional assays to show that the variant had a strong functional effect and is likely associated with increased cancer risk. Other functional/computational models validated by such biochemical assays have also shown the variant to be deleterious (Mirkovic 2004, Karchin 2007). The variant was also identified in dbSNP (ID: rs80357104) “With other allele”, but no frequency information was provided, the variant was not identified in NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) or the 1000 Genomes Browser. The variant was present in the Clinvitae database, the ClinVar database (with conflicting interpretations of pathogenicity: classified as pathogenic by Sharing Clinical Reports Project derived from Myriad reports; uncertain significance by BIC, and classification not provided by Invitae), Fanconi Anemia Mutation Database (LOVD), COSMIC (1x in a cervical tissue/squamous cell carcinoma), the BIC database (2X with unknown clinical importance), and UMD (1X with a 3-UV ”unclassified variant”). The p.Ser1722 residue is conserved across mammals and most other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Phe variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.5	D;N;.;D;.;.;N;D;D;D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0040	D;D;.;D;.;.;D;D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D;D;D;D;D;.;.;D
Polyphen		1.0, 1.0	.;D;.;.;.;D;.;.;.;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

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

Publications

LitVar

Other links and lift over

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