6-151808318-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_000125.4(ESR1):c.406C>T(p.Pro136Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000215 in 1,558,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: ESR1 NM_000125.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 2.50

Genes affected

ESR1 (HGNC:3467): (estrogen receptor 1) This gene encodes an estrogen receptor and ligand-activated transcription factor. The canonical protein contains an N-terminal ligand-independent transactivation domain, a central DNA binding domain, a hinge domain, and a C-terminal ligand-dependent transactivation domain. The protein localizes to the nucleus where it may form either a homodimer or a heterodimer with estrogen receptor 2. The protein encoded by this gene regulates the transcription of many estrogen-inducible genes that play a role in growth, metabolism, sexual development, gestation, and other reproductive functions and is expressed in many non-reproductive tissues. The receptor encoded by this gene plays a key role in breast cancer, endometrial cancer, and osteoporosis. This gene is reported to have dozens of transcript variants due to the use of alternate promoters and alternative splicing, however, the full-length nature of many of these variants remain uncertain. [provided by RefSeq, Jul 2020]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0039950907).
• BP6: Variant 6-151808318-C-T is Benign according to our data. Variant chr6-151808318-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 709059.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESR1	NM_000125.4	c.406C>T	p.Pro136Ser	missense_variant	1/8	ENST00000206249.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESR1	ENST00000206249.8	c.406C>T	p.Pro136Ser	missense_variant	1/8	1	NM_000125.4	P1

Frequencies

GnomAD3 genomes AF: 0.000961 AC: 146 AN: 151982 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000243 AC: 43 AN: 177238 Hom.: 0 AF XY: 0.000205 AC XY: 20 AN XY: 97336

Gnomad AFR exome AF: 0.00386

Gnomad AMR exome AF: 0.0000359

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000134 AC: 189 AN: 1406734 Hom.: 0 Cov.: 36 AF XY: 0.000111 AC XY: 77 AN XY: 694418

Gnomad4 AFR exome AF: 0.00508

Gnomad4 AMR exome AF: 0.000103

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000255

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000276

Gnomad4 OTH exome AF: 0.000259

GnomAD4 genome AF: 0.000960 AC: 146 AN: 152100 Hom.: 0 Cov.: 32 AF XY: 0.000847 AC XY: 63 AN XY: 74376

Gnomad4 AFR AF: 0.00325

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.0000685 Hom.: 0

Bravo AF: 0.00108

ESP6500AA AF: 0.00213 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000213 AC: 25

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ESR1 p.Pro136Ser variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs201145204) and in control databases in 72 of 208534 chromosomes at a frequency of 0.000345 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 71 of 19540 chromosomes (freq: 0.003634) and Latino in 1 of 28696 chromosomes (freq: 0.000035), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Other or South Asian populations. The p.Pro136 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	17
Dann	Benign	0.97
DEOGEN2	Benign	0.25	T;T;T;T;T;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.70	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.0040	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	N;N;N;N;.;.
MutationTaster	Benign	0.73	N;N;N;N;N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.010	N;N;N;N;N;N
REVEL	Benign	0.027
Sift	Benign	0.36	T;T;T;T;D;T
Sift4G	Benign	0.55	T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;B;.
Vest4		0.20
MVP		0.40
MPC		0.52
ClinPred		0.093	T
GERP RS		4.1
Varity_R		0.11
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs201145204; hg19: chr6-152129453;