rs80357325

chr17-43099814-G-Achr17-43099814-G-Cchr17-43099814-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_007294.4(BRCA1):c.508C>T(p.Arg170Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R170Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel U:9 B:3
• Conservation: PhyloP100: 0.685

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08125824).
• BP6: Variant 17-43099814-G-A is Benign according to our data. Variant chr17-43099814-G-A is described in ClinVar as [Benign]. Clinvar id is 55393.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43099814-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.508C>T	p.Arg170Trp	missense_variant	7/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.508C>T	p.Arg170Trp	missense_variant	7/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251458 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461236 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 726996

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000562

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Uncertain:9 Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:3 Benign:1

Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 18, 2019	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000759 -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 11, 2024	This missense variant replaces arginine with tryptophan at codon 170 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373).Functional studies have reported that this variant does not impact BRCA1 in on growth and homology-directed DNA repair assays in mouse Brca1-null embryonic stem cells (PMID: 23867111, 32546644). This variant has been reported in an individual affected with breast cancer (PMID: 25186627) and in a breast cancer case-control meta-analysis in 2/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001411). This variant also has been reported in a breast cancer case-control study and a pancreatic cancer case-control study in which this variant is absent in cases and found only in one unaffected individual in the control cohort (PMID: 30287823, 32980694). A multifactorial analysis has reported likelihood ratios for pathogenicity based on tumor pathology, co-occurrence with a pathogenic variant and family history of 0.544, 1.0673, 0.0641, respectively (PMID: 31131967). This variant has been identified in 3/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Nov 25, 2004	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 18, 2017	- -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2021	Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history including breast and ovarian cancers (Tung 2015); Published functional studies demonstrate no damaging effect to cell growth, ubiquitination, or sensitivity to cisplatin (Bouwman 2013, Starita 2015); This variant is associated with the following publications: (PMID: 23867111, 25823446, 25186627, 30287823, 33087888, 23983145, 10923033, Rodriguez2013[CaseReport], 31131967) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 03, 2019	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 01, 2023	The p.R170W variant (also known as c.508C>T), located in coding exon 6 of the BRCA1 gene, results from a C to T substitution at nucleotide position 508. The arginine at codon 170 is replaced by tryptophan, an amino acid with dissimilar properties. Functional analysis of this alteration using cDNA-based functional complementation assays in mouse embryonic stem cells demonstrated that this alteration resulted in similar proliferation rates as wildtype, and was not deleterious based on cisplatin sensitivity assays (Bouwman P et al. Cancer Discov 2013 Oct; 3(10):1142-55). This alteration was not observed in unselected male breast cancer patients but was observed with an allele frequency of 0.0001 in 12490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This variant was also reported in 2/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 05, 2023	This missense variant replaces arginine with tryptophan at codon 170 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373).Functional studies have reported that this variant does not impact BRCA1 in on growth and homology-directed DNA repair assays in mouse Brca1-null embryonic stem cells (PMID: 23867111, 32546644). This variant has been reported in an individual affected with breast cancer (PMID: 25186627) and in a breast cancer case-control meta-analysis in 2/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001411). This variant also has been reported in a breast cancer case-control study and a pancreatic cancer case-control study in which this variant is absent in cases and found only in one unaffected individual in the control cohort (PMID: 30287823, 32980694). A multifactorial analysis has reported likelihood ratios for pathogenicity based on tumor pathology, co-occurrence with a pathogenic variant and family history of 0.544, 1.0673, 0.0641, respectively (PMID: 31131967). This variant has been identified in 3/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 10, 2020	Variant summary: BRCA1 c.508C>T (p.Arg170Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251458 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.508C>T has been reported in the literature in individuals affected with Breast Cancer (example, Tung_2014) as well as an unaffected Japanese male control (Momozawa_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Bouwman_2013). These results showed no damaging effect of this variant based on cisplatin response. A recent report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as benign in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019). Six clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All clinical diagnostic laboratories classify the variant as VUS while the expert panel has settled upon a definitive classification as Benign based on posterior probability from multifactorial likelihood analysis (Plon_2008). Based on the evidence outlined above, until the consensus interpretation converges to a neutral/benign outcome, the variant was classified as uncertain significance. -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 25, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.020
Cadd	Benign	19
Dann	Benign	0.96
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.054	N
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.081	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.074	T
MutationAssessor	Benign	-0.69	N;N;N;N;.;N;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-2.1	N;N;N;D;N;D;N;N;N;D;N;.;N;N;N;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0030	D;D;T;D;D;D;D;D;D;D;T;.;D;T;D;D
Sift4G	Uncertain	0.015	D;T;T;T;T;T;.;.;D;.;T;.;D;.;D;.
Polyphen		0.0, 0.0010	.;B;.;.;.;B;.;B;.;.;B;.;.;.;.;.
Vest4		0.27
MutPred		0.41		Loss of disorder (P = 0.0062);Loss of disorder (P = 0.0062);Loss of disorder (P = 0.0062);Loss of disorder (P = 0.0062);.;Loss of disorder (P = 0.0062);.;.;.;.;Loss of disorder (P = 0.0062);Loss of disorder (P = 0.0062);Loss of disorder (P = 0.0062);.;Loss of disorder (P = 0.0062);.;
MVP		0.59
MPC		0.084
ClinPred		0.16	T
GERP RS		1.8
Varity_R		0.036
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs80357325; hg19: chr17-41251831;